Publications by authors named "Charles A Dinarello"

416 Publications

IL-37 regulates allergic inflammation by counterbalancing pro-inflammatory IL-1 and IL-33.

Allergy 2021 Aug 30. Epub 2021 Aug 30.

Division of Asthma Exacerbation &-Regulation, Priority Area Asthma & Allergy, Research Center Borstel-Leibniz Lung Center, Borstel, Germany.

Background: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation.

Methods: IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1β, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1β, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy.

Results: IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1β and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1β- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1β and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls.

Conclusion: IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1β and IL-33.
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http://dx.doi.org/10.1111/all.15072DOI Listing
August 2021

Interleukin 1 receptor antagonism abrogates acute pressure-overload induced murine heart failure.

Ann Thorac Surg 2021 Aug 19. Epub 2021 Aug 19.

Division of Cardiothoracic Surgery and Cardiovascular Research Training Institute, University of Utah, Salt Lake City, UT. Electronic address:

Background: Recent clinical trials have suggested that blockade of interleukin-1 can favorably impact patients with myocardial infarction and heart failure. However, the mechanism of how antagonism of this specific cytokine in mediating cardiac disease remains unclear. Hence, we sought to determine the influence of IL-1 blockade on acute hypertensive remodeling.

Methods: Transverse aortic constriction (TAC) was performed in C57BL mice with or without intraperitoneal administration of interleukin 1 receptor antagonism (IL-1ra). Function, structure, and molecular diagnostics were subsequently performed and analyzed.

Results: Six weeks after TAC, a progressive decline of ejection fraction and increases in LV mass and dimensions was effectively mitigated with IL-1ra. TAC resulted in an expected profile of hypertrophic markers including myosin heavy chain, atrial natriuretic peptide, and skeletal muscle actin which were all significantly lower in IL-1ra treated mice. While trichrome staining 2-weeks post TAC demonstrated similar levels of fibrosis, IL-1ra reduced expression of collagen-1, TIMP1, and periostin. Investigating the angiogenic response to pressure overload, similar levels of VEGF were observed, but IL-1ra was associated with more SDF-1. Immune cell infiltration (macrophages and lymphocytes) was also decreased in IL-1ra treated mice. Similarly, cytokine concentrations of IL-1, IL-18, and IL-6 were all reduced in IL-1ra-treated animals.

Conclusions: IL-1ra prevents the progression towards heart failure associated with acute pressure overload. This functional response was associated with reductions in mediators of fibrosis, cellular infiltration, and cytokine production. These results provide mechanistic insight into recent clinical trials and could springboard future investigations in patients with pressure-overload based cardiomyopathies.
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http://dx.doi.org/10.1016/j.athoracsur.2021.07.044DOI Listing
August 2021

Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip.

Sci Adv 2021 Aug 20;7(34). Epub 2021 Aug 20.

Department of Surgery, University of Colorado Denver, Aurora, CO, USA.

A three-dimensional microengineered human coronary artery-on-a-chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells (ECs) including pro-inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK-NF-κB signaling axis. Moreover, OSS-induced EC phenotypic changes resulted in proliferation and extracellular matrix (ECM) protein up-regulation in smooth muscle cells (SMCs) through the RANTES-mediated paracrine mechanism. IL-37 suppressed OSS-induced pro-inflammatory EndMT and thereby abrogated SMC proliferation and ECM protein remodeling. Overall, this study provides insights into endothelial heterogeneity under atheroprone shear stress and identifies the mechanistic role of a novel EC subtype in promoting adverse vascular remodeling. Further, this study demonstrates that anti-inflammatory approach is capable of mitigating vascular pathobiology evoked by atheroprone shear stress.
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http://dx.doi.org/10.1126/sciadv.abg1694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378826PMC
August 2021

Interleukins in cancer: from biology to therapy.

Nat Rev Cancer 2021 Aug 3;21(8):481-499. Epub 2021 Jun 3.

Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU, Munich, Germany.

Interleukins and associated cytokines serve as the means of communication for innate and adaptive immune cells as well as non-immune cells and tissues. Thus, interleukins have a critical role in cancer development, progression and control. Interleukins can nurture an environment enabling and favouring cancer growth while simultaneously being essential for a productive tumour-directed immune response. These properties of interleukins can be exploited to improve immunotherapies to promote effectiveness as well as to limit side effects. This Review aims to unravel some of these complex interactions.
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http://dx.doi.org/10.1038/s41568-021-00363-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173513PMC
August 2021

Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.

Blood 2021 Jun 2. Epub 2021 Jun 2.

Vita-Salute San Raffaele University & San Raffaele Scientific Institute, Milano, Italy.

Trained immunity (TI) is a pro-inflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and characterized by immunometabolic and epigenetic changes enhancing cytokine production. Maladaptive activation of TI (i.e., in the absence of infection) might result in detrimental inflammation and disease development; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. Here, we reveal oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, ECD, characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production). Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mTOR signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyper-inflammatory responses. In ECD patients, effective therapeutic strategies contrast this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (i.e., glycolysis) effectively dampens cytokine production by myeloid cells. This study reveals the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms, and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
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http://dx.doi.org/10.1182/blood.2020009594DOI Listing
June 2021

Editorial: Cytokines and Intestinal Mucosal Immunity.

Front Immunol 2021 14;12:698693. Epub 2021 May 14.

Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, United States.

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http://dx.doi.org/10.3389/fimmu.2021.698693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161542PMC
May 2021

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses.

Genome Med 2021 May 25;13(1):94. Epub 2021 May 25.

Department of Internal Medicine, Radboud Expertise Center for Immunodeficiency and Autoinflammation, and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.

Background: The interleukin (IL)-1 pathway is primarily associated with innate immunological defense and plays a major role in the induction and regulation of inflammation. Both common and rare genetic variation in this pathway underlies various inflammation-mediated diseases, but the role of rare variants relative to common variants in immune response variability in healthy individuals remains unclear.

Methods: We performed molecular inversion probe sequencing on 48 IL-1 pathway-related genes in 463 healthy individuals from the Human Functional Genomics Project. We functionally grouped common and rare variants, over gene, subpathway, and inflammatory levels and performed the Sequence Kernel Association Test to test for association with in vitro stimulation-induced cytokine responses; specifically, IL-1β and IL-6 cytokine measurements upon stimulations that represent an array of microbial infections: lipopolysaccharide (LPS), phytohaemagglutinin (PHA), Candida albicans (C. albicans), and Staphylococcus aureus (S. aureus).

Results: We identified a burden of NCF4 rare variants with PHA-induced IL-6 cytokine and showed that the respective carriers are in the 1% lowest IL-6 producers. Collapsing rare variants in IL-1 subpathway genes produces a bidirectional association with LPS-induced IL-1β cytokine levels, which is reflected by a significant Spearman correlation. On the inflammatory level, we identified a burden of rare variants in genes encoding for proteins with an anti-inflammatory function with S. aureus-induced IL-6 cytokine. In contrast to these rare variant findings which were based on different types of stimuli, common variant associations were exclusively identified with C. albicans-induced cytokine over various levels of grouping, from the gene, to subpathway, to inflammatory level.

Conclusions: In conclusion, this study shows that functionally grouping common and rare genetic variants enables the elucidation IL-1-mediated biological mechanisms, specifically, for IL-1β and IL-6 cytokine responses induced by various stimuli. The framework used in this study may allow for the analysis of rare and common genetic variants in a wider variety of (non-immune) complex phenotypes and therefore has the potential to contribute to better understanding of unresolved, complex traits and diseases.
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http://dx.doi.org/10.1186/s13073-021-00907-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145796PMC
May 2021

The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity.

Cell Rep 2021 Apr;35(1):108955

Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address:

Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.
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http://dx.doi.org/10.1016/j.celrep.2021.108955DOI Listing
April 2021

A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling.

J Biol Chem 2021 Jan-Jun;296:100630. Epub 2021 Apr 3.

Department of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address:

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.
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http://dx.doi.org/10.1016/j.jbc.2021.100630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018910PMC
July 2021

Modulation of Liver Inflammation and Fibrosis by Interleukin-37.

Front Immunol 2021 4;12:603649. Epub 2021 Mar 4.

Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité Universitätsmedizin Berlin, Berlin, Germany.

Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-β. TGF-β promotes liver fibrosis the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-β signaling cascade to modulate liver fibrogenesis. The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity. Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-β-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1β stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis. Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.
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http://dx.doi.org/10.3389/fimmu.2021.603649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970756PMC
June 2021

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.

Proc Natl Acad Sci U S A 2021 03;118(10)

Department of Medicine, University of Colorado Denver, Aurora, CO 80045;

Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples ( = 469) compared to normal skin ( = 324), with a highly significant correlation between NLRP3 and IL-1β ( < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8 T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.
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http://dx.doi.org/10.1073/pnas.2000915118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958415PMC
March 2021

Chronic HIV infection induces transcriptional and functional reprogramming of innate immune cells.

JCI Insight 2021 04 8;6(7). Epub 2021 Apr 8.

Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS-related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T cells upon bacterial, fungal, and viral stimulation. PLHIV exhibited an exacerbated proinflammatory profile in monocyte-derived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS, and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of high-sensitivity C-reactive protein and soluble CD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after more than 1 year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte-trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibited a sustained proinflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.
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http://dx.doi.org/10.1172/jci.insight.145928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119206PMC
April 2021

IL-38 prevents induction of trained immunity by inhibition of mTOR signaling.

J Leukoc Biol 2021 Feb 23. Epub 2021 Feb 23.

Department of Medicine, University of Colorado, Aurora, Colorado, USA.

Trained immunity is the acquisition of a hyperresponsive phenotype by innate immune cells (such as monocytes and macrophages) after an infection or vaccination, a de facto nonspecific memory dependent on epigenetic and metabolic reprogramming of these cells. We have recently shown that induction of trained immunity is dependent on IL-1β. Here, we show that recombinant IL-38, an anti-inflammatory cytokine of the IL-1-family, was able to induce long-term inhibitory changes and reduce the induction of trained immunity by β-glucan in vivo in C57BL/6 mice and ex vivo in their bone marrow cells. IL-38 blocked mTOR signaling and prevented the epigenetic and metabolic changes induced by β-glucan. In healthy subjects, the IL1F10 associated single nucleotide polymorphism rs58965312 correlated with higher plasma IL-38 concentrations and reduced induction of trained immunity by β-glucan ex vivo. These results indicate that IL-38 induces long-term anti-inflammatory changes and also inhibits the induction of trained immunity. Recombinant IL-38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity.
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http://dx.doi.org/10.1002/JLB.3A0220-143RRRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380748PMC
February 2021

Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases.

Autoimmun Rev 2021 Mar 20;20(3):102763. Epub 2021 Jan 20.

Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address:

The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet's syndrome, Sjogren Syndrome, and cancer. This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL-1 soluble receptor rilonacept, and the IL-1 receptor antagonist anakinra. These advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine in a broad spectrum of diseases.
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http://dx.doi.org/10.1016/j.autrev.2021.102763DOI Listing
March 2021

Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds.

Aging Cell 2021 02 22;20(2):e13309. Epub 2021 Jan 22.

Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

Aging-associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world's population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging-associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin-37 (IL-37) is a potent anti-inflammatory cytokine, and we present data demonstrating that IL-37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin-37 (IL-37) in aged mice reduces or prevents aging-associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL-37 expression decreases the surface expression of programmed cell death protein 1 (PD-1) and augments cytokine production from aged T-cells. Improved T-cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4 T-cells and Lat in CD8 T-cells when aged mice were treated with recombinant IL-37 (rIL-37) but not control immunoglobin (Control Ig). Importantly, IL-37-mediated rejuvenation of aged endogenous T-cells was also observed in aged chimeric antigen receptor (CAR) T-cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL-37 in boosting the function of aged T-cells and highlight its therapeutic potential to overcome aging-associated immunosenescence.
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http://dx.doi.org/10.1111/acel.13309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884049PMC
February 2021

IL-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex IL-1R5/IL-1R8.

Theranostics 2021 1;11(1):1-13. Epub 2021 Jan 1.

Institut de Neurociencies and Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.

Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.
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http://dx.doi.org/10.7150/thno.47435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681099PMC
August 2021

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer's disease.

Proc Natl Acad Sci U S A 2020 12 30;117(50):32145-32154. Epub 2020 Nov 30.

Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany;

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer's disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice ( = 0.001), which was completely rescued by OLT1177 fed to mice ( = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD ( = 0.007 to untreated APP/PS1). In addition, microglia were less activated ( = 0.07) and the number of plaques was reduced in the cortex ( = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.
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http://dx.doi.org/10.1073/pnas.2009680117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749353PMC
December 2020

IL-37 Expression Is Downregulated in Lesional Psoriasis Skin.

Immunohorizons 2020 11 25;4(11):754-761. Epub 2020 Nov 25.

Department of Dermatology, Aarhus University Hospital, 8000 Aarhus, Denmark.

IL-37 broadly suppresses inflammation in various disease models. However, studies of the regulation and role of IL-37 in psoriasis are limited and contradictive. Using transcriptome analysis, PCR, protein determination, and immunofluorescence, we demonstrated marked downregulation of IL-37 in biopsies from human lesional psoriasis skin compared with paired samples of nonlesional skin. Immunofluorescence analysis showed that IL-37 was localized to stratum granulosum of the epidermis. TNF-α stimulation of normal human epidermal keratinocytes led to increased expression through a p38 MAPK-mediated mechanism, whereas IL-17A, IL-17C, IL-17F, and IL-22 acted suppressively. Intradermal injection with recombinant human IL-37 into imiquimod-induced psoriasis skin of C57BL/6J mice demonstrated a trend toward a protective effect, however NS. Altogether, these results demonstrate that IL-37 is downregulated in human lesional psoriasis skin. This may be a consequence of the loss of stratum granulosum, but key cytokines in the development of psoriasis also seem to contribute to this downregulation.
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http://dx.doi.org/10.4049/immunohorizons.2000083DOI Listing
November 2020

Human recombinant interleukin-38 suppresses inflammation in mouse models of local and systemic disease.

Cytokine 2021 01 28;137:155334. Epub 2020 Oct 28.

Department of Medicine, University of Colorado Denver, Aurora, CO, USA; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Interleukin (IL)-38 belongs to the IL-1 family and is part of the IL-36 subfamily due to its binding to the IL-36 Receptor (IL-1R6). In the current study, we assessed the anti-inflammatory properties of IL-38 in murine models of arthritis and systemic inflammation. First, the anti-inflammatory properties of mouse and human IL-38 precursors were compared to forms with a truncated N-terminus. In mouse bone marrow derived dendritic cells (BMDC), human and mouse IL-38 precursors with a truncation of the two N-terminal amino acids (3-152) suppressed LPS-induced IL-6. Recombinant human IL-38 (3-152) was further investigated for its immunomodulatory potential using four murine models of inflammatory disease: streptococcal cell wall (SCW)-induced arthritis, monosodium urate (MSU) crystal-induced arthritis, MSU crystal-induced peritonitis, and systemic endotoxemia. In each of these models IL-38 significantly reduced inflammation. In SCW and MSU crystal-induced arthritis, joint swelling, inflammatory cell influx, and synovial levels of IL-1β, IL-6, and KC were reduced by 50% or greater. These suppressive properties of IL-38 in SCW-induced arthritis were independent of the anti-inflammatory co-receptor IL-1R8, as IL-38 reduced arthritis equally in IL-1R8 deficient and WT mice. In MSU crystal-induced peritonitis, IL-38 reduced hypothermia, while plasma IL-6 and KC and peritoneal KC levels were reduced by 65-70%. In the LPS endotoxemia model, IL-38 pretreatment reduced systemic IL-6, TNFα and KC. Furthermore, in ex vivo cultured bone marrow, LPS-induced IL-6, TNFα and KC were reduced by 75-90%. Overall, IL-38 exhibits broad anti-inflammatory properties in models of systemic and local inflammation and therefore may be an effective cytokine therapy.
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http://dx.doi.org/10.1016/j.cyto.2020.155334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725974PMC
January 2021

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects.

Eur J Immunol 2021 03 19;51(3):662-671. Epub 2020 Nov 19.

Department of Medicine, University of Colorado Denver, Aurora, CO, USA.

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19 B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19 B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.
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http://dx.doi.org/10.1002/eji.201948390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983920PMC
March 2021

Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.

Lancet Rheumatol 2020 May 8;2(5):e270-e280. Epub 2020 Apr 8.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands (V Klück MD, K Schraa BSc, M C P Cleophas PhD, Prof C A Dinarello MD, Prof L A B Joosten PhD); Department of Rheumatology, VieCuri Medical Center, Venlo, Netherlands (T L Th A Jansen PhD, M Janssen PhD, A Comarniceanu MD, M Efdé MD); Olatec Therapeutics, New York, NY, USA (C L Scribner MD, D B Skouras MBA); Department of Medicine, University of Colorado, Aurora, CO, USA (I W Tengesdal MSc, C Marchetti PhD, Prof C A Dinarello); and Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania (Prof L A B Joosten).

Summary:

Background: Gout flares are driven by interleukin (IL)-1β. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1β. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare.

Methods: In this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18-80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed.

Findings: Between May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving <80% of study drug and two had major protocol deviations): eight patients received 100 mg/day, seven received 300 mg/day, six received 1000 mg/day, and eight received 2000 mg/day. Between baseline and day 3, there was a mean reduction in patient-reported target joint pain of 52·4% (SD 32·94; p=0∙016) for the 100 mg/day group, 68·4% (34·29; p=0∙016) for the 300 mg/day group, 55·8% (44·90; p=0∙063) for the 1000 mg/day group, and 57·6% (38·72; p=0∙016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82·1% (22·68; p=0∙031) for the 100 mg/day group, 84·2% (16·33; p=0∙016) for the 300 mg/day group, 68·9% (34·89; p=0∙031) for the 1000 mg/day group, and 83·9% (15·44; p=0∙008) for the 2000 mg/day group, compared to baseline. 25 (73·5%) of 34 patients reported a total of 45 treatment-emergent adverse events, most of which were metabolism and nutrition disorders (17 [37·8%]) and gastrointestinal disorders (ten [22·2%]). Two serious adverse events occurred during the study, admission to hospital because of worsening of gout flare at day 3, and admission to hospital because of coronary stenosis 18 days after the patient received their last dose; these were considered moderate in severity and unrelated to the study drug.

Interpretation: Dapansutrile is a specific NLRP3 inflammasome inhibitor with a satisfactory safety profile and efficacy in the reduction of target joint pain in this study. Future studies are needed to confirm the clinical potential of dapansutrile.
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http://dx.doi.org/10.1016/s2665-9913(20)30065-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523621PMC
May 2020

Extracellular and nuclear roles of IL-37 after spinal cord injury.

Brain Behav Immun 2021 01 28;91:194-201. Epub 2020 Sep 28.

Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autonoma de Barcelona, Bellaterra, Catalonia 08193, Spain. Electronic address:

Interleukin 37 (IL-37) is an anti-inflammatory cytokine of the interleukin 1 family. Transgenic mice expressing the human form of the IL37 gene (hIL-37Tg) display protective effects in several animal models of disease. Previous data from our group revealed that IL-37 limits inflammation after spinal cord injury (SCI) and ameliorates tissue damage and functional deficits. IL-37 can exert its anti-inflammatory effects by translocating to the nucleus or acting as an extracellular cytokine. However, whether this protection after SCI is mediated by translocating to the nucleus, activating of extracellular receptors, or both, is currently unknown. In the present study, we used different transgenic animals to answer this question. We demonstrated that the beneficial effects of IL-37 on functional and histological outcomes after SCI were lost in the lack of the extracellular receptor IL-1R8, indicating that IL-37 induces protection as an extracellular cytokine. On the other hand, transgenic mice with the nuclear function of IL-37 abolished (hIL-37D20ATg) showed significant improvement in locomotor skills and myelin sparing after SCI, indicating that nuclear pathway is not required for the protective actions of IL-37. Moreover, we also showed that the therapeutic effects of the recombinant IL-37 protein are produced only in the presence of the extracellular receptor IL-1R8, further highlighting the importance of the extracellular function of this cytokine after SCI. Finally, we revealed that the administration of recombinant IL-37 protein exerted therapeutic actions when administered in the lesion site but not systemically. This work demonstrated for the first time that translocation of IL-37 to the nucleus is not required for the beneficial actions of this cytokine after SCI and highlights the importance of the extracellular signaling of IL-37 to mediate neuroprotective actions.
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http://dx.doi.org/10.1016/j.bbi.2020.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749842PMC
January 2021

Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma.

Cancers (Basel) 2020 Sep 4;12(9). Epub 2020 Sep 4.

Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 in acquired drug resistance to temozolomide (TMZ) in melanoma. The sensitivity of melanoma cells to TMZ was negatively correlated with the expression levels of -methylguanine-DNA methyltransferase (MGMT), the enzyme to repair TMZ-induced DNA lesions. When MGMT-low human melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu tumor growth in vivo. Although inflammation has been associated with drug resistance in various cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, NLRP1 might be a suitable therapeutic target in drug-resistant melanoma, as well as in other cancers.
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http://dx.doi.org/10.3390/cancers12092518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563249PMC
September 2020

IL-18 and infections: Is there a role for targeted therapies?

J Cell Physiol 2021 03 13;236(3):1638-1657. Epub 2020 Aug 13.

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.

Interleukin (IL)-18 is a pro-inflammatory cytokine belonging to the IL-1 family, first identified for its interferon-γ-inducing properties. IL-18 regulates both T helper (Th) 1 and Th2 responses. It acts synergistically with IL-12 in the Th1 paradigm, whereas with IL-2 and without IL-12 it can induce Th2 cytokine production from cluster of differentation (CD)4 T cells, natural killer (NK cells, NKT cells, as well as from Th1 cells. IL-18 also plays a role in the hemophagocytic lymphohistiocytosis, a life-threatening condition characterized by a cytokine storm that can be secondary to infections. IL-18-mediated inflammation was largely studied in animal models of bacterial, viral, parasitic, and fungal infections. These studies highlight the contribution of either IL-18 overproduction by the host or overresponsiveness of the host to IL-18 causing an exaggerated inflammatory burden and leading to tissue injury. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19). The damage in the later phase of the disease appears to be driven by a cytokine storm, including interleukin IL-1 family members and secondary cytokines like IL-6. IL-18 may participate in this hyperinflammation, as it was previously found to be able to cause injury in the lung tissue of infected animals. IL-18 blockade has become an appealing therapeutic target and has been tested in some IL-18-mediated rheumatic diseases and infantile-onset macrophage activation syndrome. Given its role in regulating the immune response to infections, IL-18 blockade might represent a therapeutic option for COVID-19, although further studies are warranted to investigate more in detail the exact role of IL-18 in SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/jcp.30008DOI Listing
March 2021

Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19.

Proc Natl Acad Sci U S A 2020 08 22;117(32):18951-18953. Epub 2020 Jul 22.

Division of Clinical Immunology, Aix-Marseille Université, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France;

Around the tenth day after diagnosis, ∼20% of patients with coronavirus disease 2019 (COVID-19)-associated pneumonia evolve toward severe oxygen dependence (stage 2b) and acute respiratory distress syndrome (stage 3) associated with systemic inflammation often termed a "cytokine storm." Because interleukin-1 (IL-1) blocks the production of IL-6 and other proinflammatory cytokines, we treated COVID-19 patients early in the disease with the IL-1 receptor antagonist, anakinra. We retrospectively compared 22 patients from three different centers in France with stages 2b and 3 COVID-19-associated pneumonia presenting with acute severe respiratory failure and systemic inflammation who received either standard-of-care treatment alone (10 patients) or combined with intravenous anakinra (12 patients). Treatment started at 300 mg⋅d for 5 d, then tapered with lower dosing over 3 d. Both populations were comparable for age, comorbidities, clinical stage, and elevated biomarkers of systemic inflammation. All of the patients treated with anakinra improved clinically ( < 0.01), with no deaths, significant decreases in oxygen requirements ( < 0.05), and more days without invasive mechanical ventilation ( < 0.06), compared with the control group. The effect of anakinra was rapid, as judged by significant decrease of fever and C-reactive protein at day 3. A mean total dose of 1,950 mg was infused with no adverse side effects or bacterial infection. We conclude that early blockade of the IL-1 receptor is therapeutic in acute hyperinflammatory respiratory failure in COVID-19 patients.
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http://dx.doi.org/10.1073/pnas.2009017117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430998PMC
August 2020

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans.

Gut 2021 Mar 22;70(3):585-594. Epub 2020 Jul 22.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria

Objective: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by ) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.

Design: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.

Results: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.

Conclusion: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.
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http://dx.doi.org/10.1136/gutjnl-2020-321375DOI Listing
March 2021

Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease.

Circ Res 2020 04 23;126(9):1260-1280. Epub 2020 Apr 23.

Department of Pharmacotherapy and Outcome Sciences, School of Pharmacy, Richmond, VA (C.M., C.A.D.).

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment-elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315937DOI Listing
April 2020

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout.

Ann Rheum Dis 2020 04 29;79(4):536-544. Epub 2020 Feb 29.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

Objective: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.

Methods: Variant identification was performed by DNA sequencing of all coding bases of using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.

Results: We identified four rare variants in in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.

Conclusion: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.
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http://dx.doi.org/10.1136/annrheumdis-2019-216233DOI Listing
April 2020

Neutralization of IL-1α ameliorates Crohn's disease-like ileitis by functional alterations of the gut microbiome.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;

Crohn's disease and ulcerative colitis are chronic and progressive inflammatory bowel diseases (IBDs) that are attributed to dysregulated interactions between the gut microbiome and the intestinal mucosa-associated immune system. There are limited studies investigating the role of either IL-1α or IL-1β in mouse models of colitis, and no clinical trials blocking either IL-1 have yet to be performed. In the present study, we show that neutralization of IL-1α by a specific monoclonal antibody against murine IL-1α was highly effective in reducing inflammation and damage in SAMP mice, mice that spontaneously develop a Crohn's-like ileitis. Anti-mouse IL-1α significantly ameliorated the established, chronic ileitis and also protected mice from developing acute DSS-induced colitis. Both were associated with taxonomic divergence of the fecal gut microbiome, which was treatment-specific and not dependent on inflammation. Anti-IL-1α administration led to a decreased ratio of to , decreased presence of species, and elevated representation of and Such modification in flora was functionally linked to the antiinflammatory effects of IL-1α neutralization, as blockade of IL-1α was not effective in germfree SAMP mice. Furthermore, preemptive dexamethasone treatment of DSS-challenged SAMP mice led to changes in flora composition without preventing the development of colitis. Thus, neutralization of IL-1α changes specific bacterial species of the intestinal microbiome, which is linked to its antiinflammatory effects. These functional findings may be of significant value for patients with IBD, who may benefit from targeted IL-1α-based therapies.
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http://dx.doi.org/10.1073/pnas.1915043116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936591PMC
December 2019
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