Publications by authors named "Jesse W Williams"

34 Publications

CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography.

Mol Pharm 2021 03 16;18(3):1386-1396. Epub 2021 Feb 16.

Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri 63110, United States.

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 , we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). pharmacokinetic evaluation through Cu radiolabeling showed extended blood circulation of Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE) showed that the three Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of human plaque specimens warrant further investigation for atherosclerosis prognosis.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01183DOI Listing
March 2021

Monocyte Recruitment, Specification, and Function in Atherosclerosis.

Cells 2020 Dec 24;10(1). Epub 2020 Dec 24.

Center for Immunology, Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

Atherosclerotic lesions progress through the continued recruitment of circulating blood monocytes that differentiate into macrophages within plaque. Lesion-associated macrophages are the primary immune cells present in plaque, where they take up cholesterol and store lipids in the form of small droplets resulting in a unique morphology termed foam cell. Recent scientific advances have used single-cell gene expression profiling, live-cell imaging, and fate mapping approaches to describe macrophage and monocyte contributions to pro- or anti-inflammatory mechanisms, in addition to functions of motility and proliferation within lesions. Yet, many questions regarding tissue-specific regulation of monocyte-to-macrophage differentiation and the contribution of recruited monocytes at stages of atherosclerotic disease progression remain unknown. In this review, we highlight recent advances regarding the role of monocyte and macrophage dynamics in atherosclerotic disease and identify gaps in knowledge that we hope will allow for advancing therapeutic treatment or prevention strategies for cardiovascular disease.
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http://dx.doi.org/10.3390/cells10010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823291PMC
December 2020

Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity.

Cell Metab 2021 Feb 4;33(2):270-282.e8. Epub 2020 Dec 4.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.
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http://dx.doi.org/10.1016/j.cmet.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858234PMC
February 2021

Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression.

Nat Immunol 2020 10 7;21(10):1194-1204. Epub 2020 Sep 7.

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (Mac) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although Mac comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce Mac-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.
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http://dx.doi.org/10.1038/s41590-020-0768-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502558PMC
October 2020

Ischemia reperfusion injury provokes adverse left ventricular remodeling in dysferlin-deficient hearts through a pathway that involves TIRAP dependent signaling.

Sci Rep 2020 08 24;10(1):14129. Epub 2020 Aug 24.

Center for Cardiovascular Research, Cardiovascular Division, Division of Cardiology, Washington University School of Medicine, 660 S. Euclid Ave,, Campus Box 8086, St. Louis, MO, 63110, USA.

Cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes following myocardial injury. Dysferlin is a protein which facilitates membrane repair by promoting membrane resealing. Although prior studies have shown that dysferlin-deficient (Dysf) mouse hearts have an impaired recovery from acute ischemia/reperfusion (I/R) injury ex vivo, the role of dysferlin in mediating the recovery from myocardial injury in vivo is unknown. Here we show that Dysf mice develop adverse LV remodeling following I/R injury secondary to the collateral damage from sustained myocardial inflammation within the infarct zone. Backcrossing Dysf mice with mice lacking signaling through the Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein (Tirap), attenuated inflammation and abrogated adverse LV remodeling following I/R injury. Subsequent studies using Poloxamer 188 (P188), a membrane resealing reagent, demonstrated that P188 did not attenuate inflammation nor prevent adverse LV remodeling in Dysf mice following I/R injury. Viewed together these studies reveal a previously unappreciated role for the importance of membrane sealing and the resolution of inflammation following myocardial injury.
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http://dx.doi.org/10.1038/s41598-020-71079-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445276PMC
August 2020

Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas.

Circ Res 2020 Jul 16;127(3):402-426. Epub 2020 Jul 16.

La Jolla Institute for Immunology, CA (C.C.H., Y.G., H.Q.D., K.L.).

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371244PMC
July 2020

Single Cell RNA Sequencing in Atherosclerosis Research.

Circ Res 2020 04 23;126(9):1112-1126. Epub 2020 Apr 23.

Laboratory of Inflammation Biology, La Jolla Institute for Immunology, CA (H.W., C.P.D., Y.G., K.L.).

Technological advances in characterizing molecular heterogeneity at the single cell level have ushered in a deeper understanding of the biological diversity of cells present in tissues including atherosclerotic plaques. New subsets of cells have been discovered among cell types previously considered homogenous. The commercial availability of systems to obtain transcriptomes and matching surface phenotypes from thousands of single cells is rapidly changing our understanding of cell types and lineage identity. Emerging methods to infer cellular functions are beginning to shed new light on the interplay of components involved in multifaceted disease responses, like atherosclerosis. Here, we provide a technical guide for design, implementation, assembly, and interpretations of current single cell transcriptomics approaches from the perspective of employing these tools for advancing cardiovascular disease research.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185048PMC
April 2020

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure.

J Clin Invest 2020 05;130(5):2644-2656

Department of Pathology and Immunology and.

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells' inflammatory phenotype may impact obesity and its complications.
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http://dx.doi.org/10.1172/JCI128687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190927PMC
May 2020

Neutrophils promote VLA-4-dependent B cell antigen presentation and accumulation within the meninges during neuroinflammation.

Proc Natl Acad Sci U S A 2019 11 7;116(48):24221-24230. Epub 2019 Nov 7.

Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110;

The success of B cell depletion therapies and identification of leptomeningeal ectopic lymphoid tissue (ELT) in patients with multiple sclerosis (MS) has renewed interest in the antibody-independent pathogenic functions of B cells during neuroinflammation. The timing and location of B cell antigen presentation during MS and its animal model experimental autoimmune encephalomyelitis (EAE) remain undefined. Using a new EAE system that incorporates temporal regulation of MHCII expression by myelin-specific B cells, we observed the rapid formation of large B cell clusters in the spinal cord subarachnoid space. Neutrophils preceded the accumulation of meningeal B cell clusters, and inhibition of CXCR2-mediated granulocyte trafficking to the central nervous system reduced pathogenic B cell clusters and disease severity. Further, B cell-restricted very late antigen-4 (VLA-4) deficiency abrogated EAE dependent on B cell antigen presentation. Together, our findings demonstrate that neutrophils coordinate VLA-4-dependent B cell accumulation within the meninges during neuroinflammation, a key early step in the formation of ELT observed in MS.
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http://dx.doi.org/10.1073/pnas.1909098116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883802PMC
November 2019

B Cell-Mediated Antigen Presentation through MHC Class II Is Dispensable for Atherosclerosis Progression.

Immunohorizons 2019 01 21;3(1):37-44. Epub 2019 Jan 21.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; and

Depletion of B cells attenuates plaque development and modulates T cell responses in mouse models of atherosclerosis, suggesting that Ag presentation by B cells may promote disease progression. Thus, we set out to determine the role of B cell-mediated MHC class II (MHC II) Ag presentation during atherosclerotic plaque development. We developed murine conditional MHC II deletion and expression systems under control of the B cell-restricted CD19 promoter in an experimental model of atherosclerosis. Mice lacking MHC II expression only on B cells exhibited systemic shifts in germinal center and marginal zone B cell populations, leading to a reduced Ab response compared with littermate control animals. However, all populations were present and normal cholesterol uptake was detected in the plasma following high-fat diet treatment. In a second model, in which conditional expression of MHC II is limited only to B cells, showed similar overall cellularity characteristics compared with mice with complete MHC II deficiency. High-fat diet feeding showed no major changes in atherosclerotic plaque size or plaque cellular content in either conditional deletion or conditional expression approaches, compared with control animals. By testing the necessity and sufficiency of MHC II on B cells in the progression of atherosclerosis, we determine that MHC II on B cells does not directly regulate lesion development in murine models.
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http://dx.doi.org/10.4049/immunohorizons.1800015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999615PMC
January 2019

A Stromal Niche Defined by Expression of the Transcription Factor WT1 Mediates Programming and Homeostasis of Cavity-Resident Macrophages.

Immunity 2019 07 20;51(1):119-130.e5. Epub 2019 Jun 20.

Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA. Electronic address:

Tissue-resident macrophages require specific milieus for the maintenance of defining gene-expression programs. Expression of the transcription factor GATA6 is required for the homeostasis, function and localization of peritoneal cavity-resident macrophages. Gata6 expression is maintained in a non-cell autonomous manner and is elicited by the vitamin A metabolite, retinoic acid. Here, we found that the GATA6 transcriptional program is a common feature of macrophages residing in all visceral body cavities. Retinoic acid-dependent and -independent hallmark genes of GATA6 macrophages were induced by mesothelial and fibroblastic stromal cells that express the transcription factor Wilms' Tumor 1 (WT1), which drives the expression of two rate-limiting enzymes in retinol metabolism. Depletion of Wt1 stromal cells reduced the frequency of GATA6 macrophages in the peritoneal, pleural and pericardial cavities. Thus, Wt1 mesothelial and fibroblastic stromal cells constitute essential niche components supporting the tissue-specifying transcriptional landscape and homeostasis of cavity-resident macrophages.
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http://dx.doi.org/10.1016/j.immuni.2019.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814267PMC
July 2019

Cytokine Circuits in Cardiovascular Disease.

Immunity 2019 04;50(4):941-954

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63139, USA. Electronic address:

Arterial inflammation is a hallmark of atherosclerosis, and appropriate management of this inflammation represents a major unmet therapeutic need for cardiovascular disease patients. Here, we review the diverse contributions of immune cells to atherosclerosis, the mechanisms of immune cell activation in this context, and the cytokine circuits that underlie disease progression. We discuss the recent application of these insights in the form of immunotherapy to treat cardiovascular disease and highlight how studies on the cardiovascular co-morbidity that arises in autoimmunity might reveal additional roles for cytokines in atherosclerosis. Currently, data point to interleukin-1β (IL-1β), tumor necrosis factor (TNF), and IL-17 as cytokines that, at least in some settings, are effective targets to reduce cardiovascular disease progression.
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http://dx.doi.org/10.1016/j.immuni.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924925PMC
April 2019

Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2-Mediated Inflammation.

Front Immunol 2018 1;9:2521. Epub 2018 Nov 1.

Committee on Molecular Pathology and Molecular Medicine, Chicago, IL, United States.

Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas-activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim-deficient T cells or Bcl-x overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non-apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2-mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation.
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http://dx.doi.org/10.3389/fimmu.2018.02521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221963PMC
October 2019

Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation.

Front Immunol 2018 30;9:2395. Epub 2018 Oct 30.

Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, United States.

Asthma is characterized by chronic airway type-2 inflammation and eosinophilia, yet the mechanisms involved in chronic, non-resolving inflammation remain poorly defined. Previously, our group has found that when Rag-deficient mice were reconstituted with Fas-deficient B6 LPR T cells and sensitized and challenged, the mice developed a prolonged type-2-mediated airway inflammation that continued for more than 6 weeks after the last antigen exposure. Surprisingly, no defect in resolution was found when intact B6 LPR mice or T cell specific Fas-conditional knockout mice were sensitized and challenged. We hypothesize that the homeostatic proliferation induced by adoptive transfer of T cells into Rag-deficient mice may be an important mechanism involved in the lack of resolution. To investigate the role of homeostatic proliferation, we induced lymphopenia in the T cell-specific Fas-conditional knockout mice by non-lethal irradiation and sensitized them when T cells began to repopulate. Interestingly, we found that defective Fas signaling on T cells plus antigen exposure during homeostatic proliferation was sufficient to induce prolonged eosinophilic airway inflammation. In conclusion, our data show that the combination of transient lymphopenia, abnormal Fas-signaling, and antigen exposure leads to the development of a prolonged airway eosinophilic inflammatory phase in our mouse model of experimental asthma.
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http://dx.doi.org/10.3389/fimmu.2018.02395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219400PMC
October 2019

Macrophage Biology, Classification, and Phenotype in Cardiovascular Disease: JACC Macrophage in CVD Series (Part 1).

J Am Coll Cardiol 2018 10;72(18):2166-2180

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Macrophages represent one of the most numerous and diverse leukocyte types in the body. Furthermore, they are important regulators and promoters of many cardiovascular disease programs. Their functions range from sensing pathogens to digesting cell debris, modulating inflammation, and producing key cytokines and other regulatory factors throughout the body. Macrophage research has undergone a renaissance in recent years, which has propelled a newfound interest in their heterogeneity as well as a new understanding of ontological differences in their development. In addition, recent technological advances such as single-cell mass-cytometry by time-of-flight have enabled phenotype and functional analyses of individual immune myeloid cells, including macrophages, at unprecedented resolution. In this Part 1 of a 4-part review series covering the macrophage in cardiovascular disease, we focus on the basic principles of macrophage development, heterogeneity, phenotype, tissue-specific differentiation, and functionality as a basis to understand their role in cardiovascular disease.
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http://dx.doi.org/10.1016/j.jacc.2018.08.2148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209330PMC
October 2018

Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models.

Circ Res 2018 10;123(10):1127-1142

From the Department of Life Sciences (K.K., D.S., M.-Y.J., H.S.J., S.H.L., S.-H.Y., J.W.N., J.-H.C.), College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea.

Rationale: Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis.

Objective: We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima.

Methods And Results: Single-cell RNA sequencing analysis of CD45 leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining-based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPYSSC foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta.

Conclusions: RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945121PMC
October 2018

Limited Macrophage Positional Dynamics in Progressing or Regressing Murine Atherosclerotic Plaques-Brief Report.

Arterioscler Thromb Vasc Biol 2018 08;38(8):1702-1710

From the Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO (J.W.W., C.M., E.E., A.E., B.T.S., L.-H.H., B.H.Z., G.J.R.).

Objective- Macrophages play important roles in the pathogenesis of atherosclerosis, but their dynamics within plaques remain obscure. We aimed to quantify macrophage positional dynamics within progressing and regressing atherosclerotic plaques. Approach and Results- In a stable intravital preparation, large asymmetrical foamy macrophages in the intima of carotid artery plaques were sessile, but smaller rounded cells nearer plaque margins, possibly newly recruited monocytes, mobilized laterally along plaque borders. Thus, to test macrophage dynamics in plaques over a longer period of time in progressing and regressing disease, we quantified displacement of nondegradable phagocytic particles within macrophages for up to 6 weeks. In progressing plaques, macrophage-associated particles appeared to mobilize to deeper layers in plaque, whereas in regressing plaques, the label was persistently located near the lumen. By measuring the distance of the particles from the floor of the plaque, we discovered that particles remained at the same distance from the floor regardless of plaque progression or regression. The apparent deeper penetration of labeled cells in progressing conditions could be attributed to monocyte recruitment that generated new superficial layers of macrophages over the labeled phagocytes. Conclusions- Although there may be individual exceptions, as a population, newly differentiated macrophages fail to penetrate significantly deeper than the limited depth they reside on initial entry, regardless of plaque progression, or regression. These limited dynamics may prevent macrophages from escaping areas with unfavorable conditions (such as hypoxia) and pose a challenge for newly recruited macrophages to clear debris through efferocytosis deep within plaque.
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http://dx.doi.org/10.1161/ATVBAHA.118.311319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202234PMC
August 2018

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood.

Circ Res 2017 Sep 10;121(6):662-676. Epub 2017 Jul 10.

From the Department of Pathology and Immunology (J.W.W., A.E., S.I., S.K., O.B., B.T.S., K.-W.K., M.W.J., J.-H.C., B.H.Z., J.R.B., G.J.R.), Department of Radiology (H.L., Y.L.), and Department of Medicine, Division of Bone and Mineral Diseases (C.S.C.), Washington University School of Medicine, St. Louis, MO; Division of Health and Sport Sciences, Missouri Baptist University, St. Louis (A.E.); Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea (J.-H.C.); and Department of Medicine, Division of Endocrinology, Medical College of Wisconsin, Milwaukee (M.G.S.-T.).

Rationale: Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective because of UCP1 (uncoupling protein 1)-dependent thermogenesis.

Objective: We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression.

Methods And Results: Using mouse models of atherosclerosis housed at 3 different ambient temperatures, we observed that cold temperature enhanced, whereas thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1. However, whereas UCP1 deficiency promoted poor glucose tolerance, thermoneutral housing enhanced glucose tolerance, and this effect held even in the context of UCP1 deficiency. In conditions of thermoneutrality, but not UCP1 deficiency, circulating monocyte counts were reduced, likely accounting for fewer monocytes entering plaques. Reductions in circulating blood monocytes were also found in a large human cohort in correlation with environmental temperature. By contrast, reduced plaque growth in mice lacking UCP1 was linked to lower cholesterol. Through application of a positron emission tomographic tracer to track CCR2 cell localization and intravital 2-photon imaging of bone marrow, we associated thermoneutrality with an increased monocyte retention in bone marrow. Pharmacological activation of β3-adrenergic receptors applied to mice housed at thermoneutrality induced UCP1 in beige fat pads but failed to promote monocyte egress from the marrow.

Conclusions: Warm ambient temperature is, like UCP1 deficiency, atheroprotective, but the mechanisms of action differ. Thermoneutrality associates with reduced monocyte egress from the bone marrow in a UCP1-dependent manner in mice and likewise may also suppress blood monocyte counts in man.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718914PMC
September 2017

A Polecat's View of Patrolling Monocytes.

Circ Res 2017 05;120(11):1699-1701

From the Department of Pathology and Immunology, Washington University in St. Louis, MO.

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http://dx.doi.org/10.1161/CIRCRESAHA.117.311021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546358PMC
May 2017

MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes.

J Exp Med 2016 09 22;213(10):1951-9. Epub 2016 Aug 22.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Peritoneal and pleural resident macrophages in the mouse share common features and in each compartment exist as two distinct subpopulations: F4/80(+) macrophages and MHC II(+) CD11c(+) macrophages. F4/80(+) macrophages derive from embryonic precursors, and their maintenance is controlled by Gata6. However, the origin and regulatory factors that maintain MHC II(+) macrophages remain unknown. Here, we show that the MHC II(+) macrophages arise postnatally from CCR2-dependent precursors that resemble monocytes. Monocytes continuously replenish this subset through adulthood. Gene expression analysis identified distinct surface markers like CD226 and revealed that the transcription factor IRF4 was selectively expressed in these macrophages relative to other organs. Monocytes first entered peritoneal or pleural cavities to become MHC II(+) cells that up-regulated CD226 and CD11c later as they continued to mature. In the absence of IRF4 or after administration of oral antibiotics, MHC II(+)CD226(-)CD11c(-) monocyte-derived cells accumulated in peritoneal and pleural cavities, but CD11c(+) CD226(+) macrophages were lost. Thus, MHC II(+) resident peritoneal and pleural macrophages are continuously replenished by blood monocytes recruited to the peritoneal and pleural cavities constitutively, starting after birth, where they require IRF4 and signals likely derived from the microbiome to fully differentiate.
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http://dx.doi.org/10.1084/jem.20160486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030807PMC
September 2016

CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability.

J Clin Invest 2016 Apr 21;126(4):1581-91. Epub 2016 Mar 21.

Lymphatic collecting vessels direct lymph into and from lymph nodes (LNs) and can become hyperpermeable as the result of a previous infection. Enhanced permeability has been implicated in compromised immunity due to reduced flow of lymph and immune cells to LNs, which are the primary site of antigen presentation to T cells. Presently, very little is known about the molecular signals that affect lymphatic collecting vessel permeability. Here, we have shown that lymphatic collecting vessel permeability is controlled by CCR7 and that the chronic hyperpermeability of collecting vessels observed in Ccr7-/- mice is followed by vessel fibrosis. Reexpression of CCR7 in DCs, however, was sufficient to reverse the development of such fibrosis. IFN regulatory factor 4-positive (IRF4+) DCs constitutively interacted with collecting lymphatics, and selective ablation of this DC subset in Cd11c-Cre Irf4fl/fl mice also rendered lymphatic collecting vessels hyperpermeable and fibrotic. Together, our data reveal that CCR7 plays multifaceted roles in regulating collecting vessel permeability and fibrosis, with one of the key players being IRF4-dependent DCs.
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http://dx.doi.org/10.1172/JCI84518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811132PMC
April 2016

Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.

Cell Host Microbe 2016 Jan;19(1):102-13

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, Fip200, Atg5, and Atg7 in myeloid cells also led to elevated basal lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases.
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http://dx.doi.org/10.1016/j.chom.2015.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714358PMC
January 2016

Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth.

Nat Immunol 2016 Feb 7;17(2):159-68. Epub 2015 Dec 7.

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.
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http://dx.doi.org/10.1038/ni.3343DOI Listing
February 2016

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses.

J Allergy Clin Immunol 2014 Sep 31;134(3):706-713.e8. Epub 2014 Jul 31.

Committee on Immunology, University of Chicago, Chicago, Ill; Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Ill; Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, Ill. Electronic address:

Background: Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown.

Objective: We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation.

Methods: C57BL/6, FcγRIII(-/-), FcRγ(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments.

Results: Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcRγ-associated receptors FcγRIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation.

Conclusion: These data identify a mechanism whereby TH2 stimuli signal through FcRγ-associated receptors on DCs to upregulate IL-33 production and induce TH2-mediated allergic airway inflammation.
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http://dx.doi.org/10.1016/j.jaci.2014.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149927PMC
September 2014

Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival.

J Exp Med 2014 Jul 14;211(8):1525-31. Epub 2014 Jul 14.

Department of Pathology and Immunology and Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110

The transcription factor Gata6 regulates proliferation and differentiation of epithelial and endocrine cells and cancers. Among hematopoietic cells, Gata6 is expressed selectively in resident peritoneal macrophages. We thus examined whether the loss of Gata6 in the macrophage compartment affected peritoneal macrophages, using Lyz2-Cre x Gata6(flox/flox) mice to tackle this issue. In Lyz2-Cre x Gata6(flox/flox) mice, the resident peritoneal macrophage compartment, but not macrophages in other organs, was contracted, with only a third the normal number of macrophages remaining. Heightened rates of death explained the marked decrease in peritoneal macrophage observed. The metabolism of the remaining macrophages was skewed to favor oxidative phosphorylation and alternative activation markers were spontaneously and selectively induced in Gata6-deficient macrophages. Gene expression profiling revealed perturbed metabolic regulators, including aspartoacylase (Aspa), which facilitates generation of acetyl CoA. Mutant mice lacking functional Aspa phenocopied the higher propensity to death and led to a contraction of resident peritoneal macrophages. Thus, Gata6 regulates differentiation, metabolism, and survival of resident peritoneal macrophages.
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http://dx.doi.org/10.1084/jem.20140570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113942PMC
July 2014

Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation.

Nat Commun 2013 ;4:2990

1] Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [2] Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [3] Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.

Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.
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http://dx.doi.org/10.1038/ncomms3990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003872PMC
July 2014

RGS3 controls T lymphocyte migration in a model of Th2-mediated airway inflammation.

Am J Physiol Lung Cell Mol Physiol 2013 Nov 27;305(10):L693-701. Epub 2013 Sep 27.

Section of Pulmonary and Critical Care, Dept. of Medicine, The Univ. of Chicago, 5841 S. Maryland Ave., MC6076, Rm. M-648, Chicago, IL 60637.

T cell migration toward sites of antigen exposure is mediated by G protein signaling and is a key function in the development of immune responses. Regulators of G protein signaling (RGS) proteins modulate G protein signaling; however, their role in the regulation of adaptive immune responses has not been thoroughly explored. Herein we demonstrated abundant expression of the Gi/Gq-specific RGS3 in activated T cells, and that diminished RGS3 expression in a T cell thymoma increased cytokine-induced migration. To examine the role of endogenous RGS3 in vivo, mice deficient in the RGS domain (RGS3(ΔRGS)) were generated and tested in an experimental model of asthma. Compared with littermate controls, the inflammation in the RGS3(ΔRGS) mice was characterized by increased T cell numbers and the striking development of perivascular lymphoid structures. Surprisingly, while innate inflammatory cells were also increased in the lungs of RGS3(ΔRGS) mice, eosinophil numbers and Th2 cytokine production were equivalent to control mice. In contrast, T cell numbers in the draining lymph nodes (dLN) were reduced in the RGS3(ΔRGS), demonstrating a redistribution of T cells from the dLN to the lungs via increased RGS3(ΔRGS) T cell migration. Together these novel findings show a nonredundant role for endogenous RGS3 in controlling T cell migration in vitro and in an in vivo model of inflammation.
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http://dx.doi.org/10.1152/ajplung.00214.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840273PMC
November 2013

ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection.

PLoS One 2013 13;8(8):e72955. Epub 2013 Aug 13.

Center for Immunobiology, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/-) mice, we found that CD4(+) T cells and ICOS(+/+) T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+)Foxp3 (+) ICOS(+) T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+) Tregs promoted survival in animals that received ICOS(-/-) T cells. Direct comparison of ICOS(-/-) Tregs to ICOS(+/+) Tregs found defects in vitro but no differences in the ability of ICOS(-/-) Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072955PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742557PMC
May 2014

IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling.

J Clin Invest 2013 May 15;123(5):2287-97. Epub 2013 Apr 15.

Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.

Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both FcγRIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of FcγRIII signaling that could contribute to this process and demonstrated that bone marrow-derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through FcγRIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.
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http://dx.doi.org/10.1172/JCI63802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635716PMC
May 2013

Autoreactive T and B cells induce the development of bronchus-associated lymphoid tissue in the lung.

Am J Respir Cell Mol Biol 2013 Apr;48(4):406-14

Center for Immunobiology, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Studies in humans have found that the incidence of bronchus-associated lymphoid tissue (BALT) correlates with the severity of lung injury. However, the mechanisms underlying the development of BALT during systemic autoimmunity remain unknown. We have determined whether systemic autoimmunity in a murine model of autoimmune arthritis can promote the development of BALT by generating a novel murine model derived from K/BxN mice. Transgenic mice with the KRN T-cell receptor specific for the autoantigen, glucose-6-phosphate isomerase (GPI), were crossed with GPI-specific immunoglobulin heavy and light chain knock-in mice, producing mice with a majority of T and B cells specific for the same autoantigen. We found that 67% of these mice demonstrated lymphocytic infiltration in the lungs, localized to either the perivascular or peribronchial regions. Fifty percent of the mice with lymphocytic infiltration manifested lymphoid-like lesions resembling BALT, with distinct T and B cell follicles. The lungs from mice with lymphoid infiltrates had increased numbers of cytokine-producing T cells, including IL-17A(+) T cells and increased major histocompatibility complex Class II expression on B cells. Interestingly, challenge with bleomycin failed to elicit a significant fibrotic response, compared with wild-type control mice. Our data suggest that systemic autoreactivity promotes ectopic lymphoid tissue development in the lung through the cooperation of autoreactive T and B cells. However, these BALT-like lesions may not be sufficient to promote fibrotic lung disease at steady state or after inflammatory challenge.
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http://dx.doi.org/10.1165/rcmb.2012-0065OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653607PMC
April 2013