Publications by authors named "Jean-Philippe Girard"

69 Publications

Targeting androgen signaling in ILC2s protects from IL-33-driven lung inflammation, independently of KLRG1.

J Allergy Clin Immunol 2021 May 5. Epub 2021 May 5.

Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address:

Background: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms.

Objectives: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1).

Methods: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice.

Results: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes.

Conclusions: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.
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http://dx.doi.org/10.1016/j.jaci.2021.04.029DOI Listing
May 2021

High endothelial venules (HEVs) in immunity, inflammation and cancer.

Angiogenesis 2021 May 6. Epub 2021 May 6.

Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.

High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body's own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn's disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79 tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3 T cell-rich areas or CD20 B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.
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http://dx.doi.org/10.1007/s10456-021-09792-8DOI Listing
May 2021

Exclusive B-cell phenotype of primary prostatic lymphomas: a potential role of chronic prostatitis.

Histopathology 2020 Apr 17;76(5):767-773. Epub 2020 Mar 17.

Department of Pathology, Institut Universitaire du Cancer de Toulouse, Toulouse, France.

Aims: Primary prostatic lymphomas (PPL) is exceedingly rare. The aim of this study was to investigate the largest series of PPL obtained from a nationwide expert pathologist network, and thus try to understand the pathophysiology of these tumours.

Methods And Results: Up to 66 000 lymphoma cases have been collected and submitted for central expert review by the French Lymphopath network. We confirm the low frequency of PPL (n = 77; 0.12%), all cases being of B-cell origin. Diffuse large B-cell lymphoma and small lymphocytic lymphoma were the most frequent subtypes, comprising 31% and 26% of cases respectively, followed by mucosa-associated lymphoid tissue (MALT)/lymphoplasmacytic lymphoma (19%), follicular lymphoma (12%), mantle cell lymphoma (6%), Burkitt lymphoma (4%), and unclassified lymphoma (1%). Clinical data obtained in 25 cases suggests that PPLs are rather indolent tumours. Our hypothesis for B-cell recruitment in the prostatic tissue was derived from the observation in chronic inflammation (prostatitis) of frequent heterotopic proliferation of high endothelial venules (HEVs). The latter are dedicated to lymphocyte entry into secondary lymphoid organs, here putatively driving circulating clonal B-lymphocytes from the blood into the inflamed prostate. This may account for the relatively high incidence of small lymphocytic lymphoma consistently reported in series of primary or secondary prostatic lymphoma. As in other organs or glands, chronic inflammation may promote antigen-dependent intraprostatic MALT lymphoma and diffuse large B-cell lymphoma development.

Conclusions: PPLs are exclusively of B-cell origin, and chronic inflammation resulting from the proliferation of high endothelial venules could play some role in their development.
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http://dx.doi.org/10.1111/his.14045DOI Listing
April 2020

RelB Deficiency in Dendritic Cells Protects from Autoimmune Inflammation Due to Spontaneous Accumulation of Tissue T Regulatory Cells.

J Immunol 2019 11 2;203(10):2602-2613. Epub 2019 Oct 2.

Zentrum Allergie und Umwelt, Technische Universität und Helmholtz Zentrum München, 85764 Neuherberg, Germany;

Foxp3 regulatory T cells are well-known immune suppressor cells in various settings. In this study, we provide evidence that knockout of the gene in dendritic cells (DCs) of C57BL/6 mice results in a spontaneous and systemic accumulation of Foxp3 T regulatory T cells (Tregs) partially at the expense of microbiota-reactive Tregs. Deletion of does not fully recapitulate this phenotype, indicating that alternative NF-κB activation via the RelB/p52 complex is not solely responsible for Treg accumulation. Deletion of RelB in DCs further results in an impaired oral tolerance induction and a marked type 2 immune bias among accumulated Foxp3 Tregs reminiscent of a tissue Treg signature. Tissue Tregs were fully functional, expanded independently of IL-33, and led to an almost complete Treg-dependent protection from experimental autoimmune encephalomyelitis. Thus, we provide clear evidence that RelB-dependent pathways regulate the capacity of DCs to quantitatively and qualitatively impact on Treg biology and constitute an attractive target for treatment of autoimmune diseases but may come at risk for reduced immune tolerance in the intestinal tract.
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http://dx.doi.org/10.4049/jimmunol.1801530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826119PMC
November 2019

[Interleukin-33: from biology to potential treatments].

Med Sci (Paris) 2019 May 22;35(5):440-451. Epub 2019 May 22.

Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 205, route de Narbonne, 31077 Toulouse, France.

Interleukin-33 is a member of the IL-1 cytokine family, expressed in the nucleus of endothelial cells and epithelial cells of barrier tissues. After cellular damage, IL-33 is released in the extracellular space and functions as an alarmin that alerts the immune system. IL-33 plays a critical role in type-2 innate immunity and allergic inflammation, by activating various target cells including mast cells and innate lymphoid cells that secrete high amounts of IL-5 and IL-13, two cytokines involved in allergic reactions. Recent studies suggest that IL-33 can also play other important roles, for example in homeostasis and during viral infection. It is implicated in numerous diseases, including allergic, inflammatory and infectious diseases and it constitutes a promising therapeutic target for treatment of severe asthma.
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http://dx.doi.org/10.1051/medsci/2019078DOI Listing
May 2019

Innate lymphoid cells in asthmatic patients.

J Allergy Clin Immunol 2019 05 27;143(5):1739-1741. Epub 2019 Mar 27.

Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.03.011DOI Listing
May 2019

Single-Cell Analysis Reveals Heterogeneity of High Endothelial Venules and Different Regulation of Genes Controlling Lymphocyte Entry to Lymph Nodes.

Cell Rep 2019 03;26(11):3116-3131.e5

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address:

High-endothelial venules (HEVs) are specialized blood vessels allowing recirculation of naive lymphocytes through lymphoid organs. Here, using full-length, single-cell RNA sequencing, RNA fluorescence in situ hybridization (FISH), flow cytometry, and immunohistofluorescence, we reveal the heterogeneity of HEVs in adult mouse peripheral lymph nodes (PLNs) under conditions of homeostasis, antigenic stimulation, and after inhibition of lymphotoxin-β receptor (LTβR) signaling. We demonstrate that HEV endothelial cells are in an activated state during homeostasis, and we identify the genes characteristic of the differentiated HEV phenotype. We show that LTβR signaling regulates many HEV genes and pathways in resting PLNs and that immune stimulation induces a global and temporary inflammatory phenotype in HEVs without compromising their ability to recruit naive lymphocytes. Most importantly, we uncover differences in the regulation of genes controlling lymphocyte trafficking, Glycam1, Fut7, Gcnt1, Chst4, B3gnt3, and Ccl21a, that have implications for HEV function and regulation in health and disease.
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http://dx.doi.org/10.1016/j.celrep.2019.02.042DOI Listing
March 2019

Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33.

Nat Immunol 2018 04 19;19(4):375-385. Epub 2018 Mar 19.

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.

Allergic inflammation has crucial roles in allergic diseases such as asthma. It is therefore important to understand why and how the immune system responds to allergens. Here we found that full-length interleukin 33 (IL-33), an alarmin cytokine with critical roles in type 2 immunity and asthma, functioned as a protease sensor that detected proteolytic activities associated with various environmental allergens across four kingdoms, including fungi, house dust mites, bacteria and pollens. When exposed to allergen proteases, IL-33 was rapidly cleaved in its central 'sensor' domain, which led to activation of the production of type 2 cytokines in group 2 innate lymphoid cells. Preventing cleavage of IL-33 reduced allergic airway inflammation. Our findings reveal a molecular mechanism for the rapid induction of allergic type 2 inflammation following allergen exposure, with important implications for allergic diseases.
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http://dx.doi.org/10.1038/s41590-018-0067-5DOI Listing
April 2018

Endogenous IL-33 Contributes to Kidney Ischemia-Reperfusion Injury as an Alarmin.

J Am Soc Nephrol 2018 04 7;29(4):1272-1288. Epub 2018 Feb 7.

Unité Mixte de Recherche 1082, Institut National de la Santé et de la Recherche Médicale, Poitiers, France.

Inflammation is a prominent feature of ischemia-reperfusion injury (IRI), which is characterized by leukocyte infiltration and renal tubular injury. However, signals that initiate these events remain poorly understood. We examined the role of the nuclear alarmin IL-33 in tissue injury and innate immune response triggered by experimental kidney ischemia-reperfusion. In wild-type mice, we found that IL-33 was constitutively expressed throughout the kidney in peritubular and periglomerular spaces, mainly by microvascular endothelial cells, from which it was released immediately during IRI. Compared with wild-type mice, mice lacking IL-33 (IL-33) exhibited reductions in early tubular cell injury and subsequent renal infiltration of IFN-/IL-17A-producing neutrophils, with preservation of renal functions. This protection associated with decreased renal recruitment of myeloid dendritic cells, natural killer (NK) cells, and invariant natural killer T (iNKT) cells, the latter of which were reported as deleterious in IRI. Increases in the level of circulating IL-12, a key IL-33 cofactor, and the expression of ST2, an IL-33-specific receptor, on the surface of iNKT cells preceded the IL-33- and iNKT cell-dependent phase of neutrophil infiltration. Furthermore, IL-33 directly targeted iNKT cells , inducing IFN- and IL-17A production. We propose that endogenous IL-33 is released as an alarmin and contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, resulting in neutrophil infiltration and activation at the injury site. Our findings show a novel molecular mediator contributing to innate immune cell recruitment induced by renal ischemia-reperfusion and may provide therapeutic insights into AKI associated with renal transplantation.
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http://dx.doi.org/10.1681/ASN.2017060650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875946PMC
April 2018

Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family.

Immunol Rev 2018 01;281(1):154-168

Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.

Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8 T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.
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http://dx.doi.org/10.1111/imr.12619DOI Listing
January 2018

Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production.

Immunity 2017 11;47(5):928-942.e7

Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.

Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion.
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http://dx.doi.org/10.1016/j.immuni.2017.10.015DOI Listing
November 2017

IL-33-expanded human Vγ9Vδ2 T cells have anti-lymphoma effect in a mouse tumor model.

Eur J Immunol 2017 12 29;47(12):2137-2141. Epub 2017 Sep 29.

INSERM UMR1037-Cancer Research Center of Toulouse, Toulouse, France.

From several years, the anticancer effects of Vγ9 T lymphocytes make these cells good candidates for cancer immunotherapies. However, the proved efficacy of γδ Τ cell-based cancer immunotherapies in some clinical trials was minimized due to the inherent toxicity of IL-2, which is essential for the combination therapy with Phosphoantigen (PAg). Recently, we showed that IL-33, a γ chain receptor-independent cytokine, was able to induce the in vitro proliferation of PAg-activated Vγ9 T cells, which were fully functional expressing IFN-γ and TNF-α and showing in vitro anti-tumor cytotoxicity. We proposed IL-33 as an alternative to IL-2 for Vγ9 T cell-based cancer immunotherapies, and have therefore evaluated the efficacy of this cytokine in preclinical investigations. This study shows that human Vγ9 T cells are able to proliferate in a mouse model with the combination of PAg and rhIL-33, and that IL-33-expanded Vγ9 T cells can prevent tumor growth in a mouse lymphoma model.
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http://dx.doi.org/10.1002/eji.201747093DOI Listing
December 2017

Endogenous IL-33 has no effect on the progression of fibrosis during experimental steatohepatitis.

Oncotarget 2017 Jul;8(30):48563-48574

Institut National de la Santé et de la Recherche Médicale, Institut de Recherche Santé Environnement & Travail, Université de Rennes, Rennes, France.

Interleukin (IL)-33 has been recently reported to be strongly pro-fibrogenic in various models of liver disease. Our aim was to study the role of endogenous IL-33 in a diet-induced model of steatohepatitis. IL-33 deficient mice and wild type (WT) littermates received a high-fat diet (HFD), or a standard diet for 12 weeks. The HFD-induced steatohepatitis was associated with an upregulation of IL-33 transcripts and protein. An insulin tolerance test revealed lower systemic insulin sensitivity in IL-33-/-HFD mice than in WT-HFD mice. Nevertheless, IL-33 deficiency did not affect the severity of liver inflammation by histological and transcriptomic analyses, nor the quantity of liver fibrosis. Livers from HFD mice had more myeloid populations, markedly fewer NKT cells and higher proportion of ST2+ Treg cells and ST2+ type 2 innate lymphoid cells (ILC2), all unaffected by IL-33 deficiency. In conclusion, deficiency of endogenous IL-33 does not affect the evolution of experimental diet-induced steatohepatitis towards liver fibrosis.
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http://dx.doi.org/10.18632/oncotarget.18335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564708PMC
July 2017

Endogenous IL-33 Deficiency Exacerbates Liver Injury and Increases Hepatic Influx of Neutrophils in Acute Murine Viral Hepatitis.

Mediators Inflamm 2017 4;2017:1359064. Epub 2017 May 4.

Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), 35043 Rennes, France.

The alarmin IL-33 has been described to be upregulated in human and murine viral hepatitis. However, the role of endogenous IL-33 in viral hepatitis remains obscure. We aimed to decipher its function by infecting IL-33-deficient mice (IL-33 KO) and their wild-type (WT) littermates with pathogenic mouse hepatitis virus (L2-MHV3). The IL-33 KO mice were more sensitive to L2-MHV3 infection exhibiting higher levels of AST/ALT, higher tissue damage, significant weight loss, and earlier death. An increased depletion of B and T lymphocytes, NKT cells, dendritic cells, and macrophages was observed 48 h postinfection (PI) in IL-33 KO mice than that in WT mice. In contrast, a massive influx of neutrophils was observed in IL-33 KO mice at 48 h PI. A transcriptomic study of inflammatory and cell-signaling genes revealed the overexpression of IL-6, TNF, and several chemokines involved in recruitment/activation of neutrophils (CXCL2, CXCL5, CCL2, and CCL6) at 72 h PI in IL-33 KO mice. However, the IFN was strongly induced in WT mice with less profound expression in IL-33 KO mice demonstrating that endogenous IL-33 regulated IFN expression during L2-MHV3 hepatitis. In conclusion, we demonstrated that endogenous IL-33 had multifaceted immunoregulatory effect during viral hepatitis via induction of IFN, survival effect on immune cells, and infiltration of neutrophils in the liver.
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http://dx.doi.org/10.1155/2017/1359064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457781PMC
March 2018

Androgen signaling negatively controls group 2 innate lymphoid cells.

J Exp Med 2017 06 8;214(6):1581-1592. Epub 2017 May 8.

Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Institut National de la Santé et de la Recherche Medicale (INSERM), Centre National de la Recherche Scientifique (CNRS), UPS, 31300 Toulouse, France

Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33-mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33-driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.
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http://dx.doi.org/10.1084/jem.20161807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461006PMC
June 2017

Interleukin-33 in health and disease.

Nat Rev Immunol 2016 11 19;16(11):676-689. Epub 2016 Sep 19.

Starzl Transplantation Institute, and the Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

Interleukin-33 (IL-33) - a member of the IL-1 family - was originally described as an inducer of type 2 immune responses, activating T helper 2 (T2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (T) cells, T1 cells, CD8 T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans.
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http://dx.doi.org/10.1038/nri.2016.95DOI Listing
November 2016

Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells.

Sci Rep 2016 10 3;6:34255. Epub 2016 Oct 3.

Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France.

IL-33 is a nuclear cytokine from the IL-1 family that plays important roles in health and disease. Extracellular IL-33 activates a growing number of target cells, including group 2 innate lymphoid cells, mast cells and regulatory T cells, but it remains unclear whether intracellular nuclear IL-33 has additional functions in the nucleus. Here, we used a global proteomic approach based on high-resolution mass spectrometry to compare the extracellular and intracellular roles of IL-33 in primary human endothelial cells, a major source of IL-33 protein in human tissues. We found that exogenous extracellular IL-33 cytokine induced expression of a distinct set of proteins associated with inflammatory responses in endothelial cells. In contrast, knockdown of endogenous nuclear IL-33 expression using two independent RNA silencing strategies had no reproducible effect on the endothelial cell proteome. These results suggest that IL-33 acts as a cytokine but not as a nuclear factor regulating gene expression in endothelial cells.
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http://dx.doi.org/10.1038/srep34255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5046127PMC
October 2016

In Vivo Expansion of Activated Foxp3+ Regulatory T Cells and Establishment of a Type 2 Immune Response upon IL-33 Treatment Protect against Experimental Arthritis.

J Immunol 2016 09 29;197(5):1708-19. Epub 2016 Jul 29.

INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93000 Bobigny, France;

IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen-induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis. In contrast, a late IL-33 injection had no effect. The cellular mechanism involved in protection was related to an enhanced type 2 immune response, including the expansion of eosinophils, Th2 cells, and type 2 innate lymphoid cells, associated with an increase in type 2 cytokine levels in the serum of IL-33-treated mice. Moreover, our work strongly highlights the interplay between IL-33 and regulatory T cells (Tregs), demonstrated by the dramatic in vivo increase in Treg frequencies after IL-33 treatment of CIA. More importantly, Tregs from IL-33-treated mice displayed enhanced capacities to suppress IFN-γ production by effector T cells, suggesting that IL-33 not only favors Treg proliferation but also enhances their immunosuppressive properties. In concordance with these observations, we found that IL-33 induced the emergence of a CD39(high) Treg population in a ST2L-dependent manner. Our findings reveal a powerful anti-inflammatory mechanism by which IL-33 administration inhibits arthritis development.
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http://dx.doi.org/10.4049/jimmunol.1502124DOI Listing
September 2016

Ablation of interaction between IL-33 and ST2+ regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration.

Am J Physiol Gastrointest Liver Physiol 2016 08 23;311(2):G313-23. Epub 2016 Jun 23.

Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;

The IL-33/ST2 axis plays a protective role in T-cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL-33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33(-/-) mice displayed more severe Con A liver injury than wild-type (WT) mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33(-/-) mice was associated with significantly higher levels of TNF-α and IL-1β and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL-10) and IL-17 was not significantly varied between WT and IL-33(-/-) mice following Con A-hepatitis. The percentage of CD25(+) NK cells was significantly higher in the livers of IL-33(-/-) mice than in WT mice in association with upregulated expression of CXCR3 in the liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33(-/-) mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4(+) and CD8(+) T cells, and the frequency of ST2(+) Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2(+) Treg cells and control of NK cells.
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http://dx.doi.org/10.1152/ajpgi.00097.2016DOI Listing
August 2016

Collagen-induced arthritis and imiquimod-induced psoriasis develop independently of interleukin-33.

Arthritis Res Ther 2016 06 18;18(1):143. Epub 2016 Jun 18.

INSERM, UMR 1125, 93017, Bobigny, France.

Background: Interleukin (IL)-33 is a dual cytokine with both an alarmin role and a T helper 2 cell (Th2)-like inducing effect. It is involved in the pathogenesis of rheumatoid arthritis (RA) and its models; we recently demonstrated that exogenous IL-33 could inhibit collagen-induced arthritis (CIA) in C57BL/6 mice. However, its pathophysiological role in RA is unclear. Indeed, mice deficient in the IL-33 receptor ST2 show reduced susceptibility to arthritis, and the disease is not modified in IL-33-deficient mice. We examined the immune response in wild-type (WT) and IL-33-deficient mice with CIA. To further understand the role of endogenous IL-33 in inflammatory diseases, we studied its role in a skin psoriasis model. Mice on a C57BL/6 background were deficient in IL-33 but expressed lacZ under the IL-33 promoter. Therefore, IL-33 promotor activity could be analyzed by lacZ detection and IL-33 gene expression was analyzed by X-Gal staining in various mice compartments. Frequencies of CD4(+)FoxP3(+) regulatory T cells (Tregs) and Th1 and Th17 cells were evaluated by flow cytometry in WT and IL-33(-/-) mice. Bone resorption was studied by evaluating osteoclast activity on a synthetic mineral matrix. Psoriasis-like dermatitis was induced by application of imiquimod to the skin of mice.

Results: Severity of CIA was similar in IL-33(-/-) and WT littermates. Joints of IL-33(-/-) mice with CIA showed IL-33 promotor activity. In mice with CIA, frequencies of Tregs, Th1 and Th17 in the spleen or lymph nodes did not differ between the genotypes; osteoclast activity was higher but not significantly in IL-33(-/-) than WT mice. Psoriasis development did not differ between the genotypes.

Conclusions: Despite its expression in the synovium of arthritic mice and normal keratinocytes, IL-33 is not required for CIA development in arthritis or psoriasis. Its absence does not induce a T cell shift toward Th1, Th17 or Treg subpopulations. Altogether, these data and our previous ones, showing that exogenous IL-33 can almost completely inhibit CIA development, suggest that this cytokine is not crucial for development of chronic inflammation. Studies of RA patients are needed to determine whether treatment targeting the IL-33/ST2 axis would be effective.
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http://dx.doi.org/10.1186/s13075-016-1042-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912820PMC
June 2016

TCRVγ9 γδ T Cell Response to IL-33: A CD4 T Cell-Dependent Mechanism.

J Immunol 2016 Jan 25;196(1):493-502. Epub 2015 Nov 25.

INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and

The availability of specific stimuli to induce the anticancer cytotoxicity of human TCRVγ9-expressing T lymphocytes has allowed the development of γδ T cell-based cancer immunotherapies. However, the stringent dependence of such strategies on the inherently toxic IL-2 has raised safety concerns for patients, justifying a search for alternative methods for inducing γδ T cell stimulation. IL-33 is a γ-chain receptor-independent cytokine of the IL-1 superfamily that is expressed by endothelial cells from a tumor microenvironment and can sustain Th1 and Th2 immune responses. Therefore, we investigated its ability to support the stimulation of human TCRVγ9(+) γδ T cells. In this study, we report that IL-33 efficiently sustained the in vitro activation of Vγ9 T lymphocytes by synthetic phosphoantigens, zoledronate, and a BTN3A1 Ab in the absence of an exogenous supply of IL-2. IL-33 was as potent as IL-2 in allowing the proliferative amplification of Vγ9 T cells isolated from PBMC following activation by the synthetic phosphoantigen bromohydrin pyrophosphate. IL-33 also induced an identical maturation into TNF-α- and IFN-γ-producing Th1 effector memory cells, and IL-33-stimulated cells showed an equivalent cytotoxicity for various tumor cells in vitro. Finally, we found that the bioactivity of IL-33 on the Vγ9 T cell was indirectly mediated through contact with CD4 T cells and IL-2 production by CD4 T cells and Vγ9 T cells themselves. These data posit IL-33 as an alternative to IL-2 for Vγ9 T cell-based cancer immunotherapies.
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http://dx.doi.org/10.4049/jimmunol.1500260DOI Listing
January 2016

L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo.

Blood 2015 Sep 10;126(11):1336-45. Epub 2015 Jul 10.

Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Toulouse, France;

B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Lymph nodes (LNs) are sites of malignant proliferation and LN enlargement is associated with poor prognosis in the clinics. The LN microenvironment is believed to favor disease progression by promoting CLL cell growth and drug resistance. A better understanding of the mechanisms regulating trafficking of CLL cells to LNs is thus urgently needed. Here, we studied the first step of CLL cell migration to LNs, their interaction with high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation in lymphoid organs. We observed that the density of HEV blood vessels was increased in CLL LNs and that CD20(+) CLL cells accumulated within HEV pockets, suggesting intense trafficking. We used intravital imaging to visualize the behavior of human CLL cells within the mouse LN microcirculation, and discovered that CLL cells bind to HEVs in vivo via a multistep adhesion cascade, which involves rolling, sticking, and crawling of the leukemic cells on the endothelium. Functional analyses revealed that the lymphocyte homing receptor L-selectin (CD62L) is the key factor controlling the binding of CLL cells to HEV walls in vivo. Interestingly, L-selectin expression was decreased on CLL cells from patients treated with idelalisib, a phosphoinositide-3-kinase δ inhibitor recently approved for CLL therapy. Interference with L-selectin-mediated trafficking in HEVs could represent a novel strategy to block dissemination of CLL cells to LNs and increase the efficacy of conventional therapy.
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http://dx.doi.org/10.1182/blood-2015-02-626291DOI Listing
September 2015

IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection.

J Immunol 2015 Jun 29;194(12):5948-52. Epub 2015 Apr 29.

Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143;

NK cells provide important host defense against viruses and can differentiate into self-renewing memory NK cells after infection, alloantigen stimulation, and cytokine stimulation. In this study, we investigated the role of the IL-33 receptor ST2 in the differentiation of NK cells during mouse CMV (MCMV) infection. Although ST2-deficient (Il1rl1 (-/-)) Ly49H(+) NK cells develop normally and differentiate into memory cells after MCMV infection, naive and memory Il1rl1 (-/-) Ly49H(+) NK cells exhibited profound defects in MCMV-specific expansion, resulting in impaired protection against MCMV challenge. Additionally, IL-33 enhanced m157 Ag-specific proliferation of Ly49H(+) NK cells in vitro. Thus, an IL-33/ST2 signaling axis in NK cells contributes to host defense against MCMV.
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http://dx.doi.org/10.4049/jimmunol.1500424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458425PMC
June 2015

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells.

Proc Natl Acad Sci U S A 2014 Oct 13;111(43):15502-7. Epub 2014 Oct 13.

Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and

Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33(95-270), IL-33(107-270), and IL-33(109-270), were 30-fold more potent than full-length human IL-33(1-270) for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1410700111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217470PMC
October 2014

IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy.

Curr Opin Immunol 2014 Dec 29;31:31-7. Epub 2014 Sep 29.

CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, F-31077 Toulouse, France; Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France. Electronic address:

IL-33 is a nuclear cytokine from the IL-1 family constitutively expressed in epithelial barrier tissues and lymphoid organs, which plays important roles in type-2 innate immunity and human asthma. Recent studies indicate that IL-33 induces production of large amounts of IL-5 and IL-13 by group 2 innate lymphoid cells (ILC2s), for initiation of allergic inflammation shortly after exposure to allergens or infection with parasites or viruses. IL-33 appears to function as an alarmin (alarm signal) rapidly released from producing cells upon cellular damage or cellular stress. In this review, we discuss the cellular sources, mode of action and regulation of IL-33, and we highlight its crucial roles in vivo with particular emphasis on results obtained using IL33-deficient mice.
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http://dx.doi.org/10.1016/j.coi.2014.09.004DOI Listing
December 2014

BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34+ progenitors from chronic myeloid leukemia patients.

Cancer Res 2014 May 27;74(10):2669-76. Epub 2014 Mar 27.

Authors' Affiliations: INSERM UMR S935, Poitiers and Villejuif; Université Paris-Sud 11, Orsay; INSERM U1082; Université de Poitiers; Service d'Immunologie et Inflammation; CHU de Poitiers; Etablissement Français du Sang Centre-Atlantique, site de Poitiers; Service d'Oncologie Hématologique et Thérapie Cellulaire; INSERM-CIC1402; Service de Cancérologie Biologique; Service d'Hématologie et d'Oncologie Biologique, Poitiers; CNRS, Institut de Pharmacologie et de Biologie Structurale; and Université de Toulouse, Toulouse, FranceAuthors' Affiliations: INSERM UMR S935, Poitiers and Villejuif; Université Paris-Sud 11, Orsay; INSERM U1082; Université de Poitiers; Service d'Immunologie et Inflammation; CHU de Poitiers; Etablissement Français du Sang Centre-Atlantique, site de Poitiers; Service d'Oncologie Hématologique et Thérapie Cellulaire; INSERM-CIC1402; Service de Cancérologie Biologique; Service d'Hématologie et d'Oncologie Biologique, Poitiers; CNRS, Institut de Pharmacologie et de Biologie Structurale; and Université de Toulouse, Toulouse, FranceAuthors' Affiliations: INSERM UMR S935, Poitiers and Villejuif; Université Paris-Sud 11, Orsay; INSERM U1082; Université de Poitiers; Service d'Immunologie et Inflammation; CHU de Poitiers; Etablissement Français du Sang Centre-Atlantique, site de Poitiers; Service d'Oncologie Hématologique et Thérapie Cellulaire; INSERM-CIC1402; Service de Cancérologie Biologique; Service d'Hématologie et d'Oncologie Biologique, Poitiers; CNRS, Institut de Pharmacologie et de Biologie Structurale; and Université de Toulouse, Toulouse, FranceAuthors' Affiliations: INSERM UMR S935, Poitiers and Villejuif; Université Paris-Sud 11, Orsay; INSERM U1082; Université de Poitiers; Service d'Immunologie et Inflammation; CHU de Poitiers; Etablissement Français du Sang Centre-Atlantique, site de Poitiers; Service d'Oncologie Hématologique et Thérapie Cellulaire; INSERM-CIC1402; Service de Cancérologie Biologique; Service d

Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-2797DOI Listing
May 2014

The alarmin concept applied to human renal transplantation: evidence for a differential implication of HMGB1 and IL-33.

PLoS One 2014 20;9(2):e88742. Epub 2014 Feb 20.

Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France.

The endogenous molecules high mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been identified as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. We analysed serum and urinary HMGB1 and IL-33 levels, all determined by enzyme-linked immunosorbent assay, in a cohort of 26 deceased renal transplant recipients. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to those before treatment. Moreover, both serum and urinary IL-33 (but not HMGB1) increase was positively correlated with cold ischemia time, from 30 min to 3 days post-transplantation. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Finally, we postulate that leukocytes from renal recipient patients are targeted by both HMGB1 and IL-33, as suggested by increased transcription of their respective receptors (TLR2/4 and ST2L) shortly after transplantation. Consistent with this view, we found that iNKT cells, an innate-like T cell subset involved in IRI and targeted by IL-33 but not by HMGB1 was activated 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088742PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930579PMC
January 2015

Regulation of tumor-associated high-endothelial venules by dendritic cells: A new opportunity to promote lymphocyte infiltration into breast cancer?

Oncoimmunology 2013 Nov 10;2(11):e26470. Epub 2013 Oct 10.

CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale); Toulouse, France ; Université de Toulouse; UPS; IPBS; Toulouse, France.

Accumulating evidence suggests that high-endothelial venules (HEVs) represent major gateways for the infiltration of lymphocytes within neoplastic lesions. However, the origin of these vessels in human neoplasms remains elusive. We have recently discovered a link between lymphotoxin β-producing dendritic cells and tumor-associated HEVs.
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http://dx.doi.org/10.4161/onci.26470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897501PMC
November 2013

Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.

J Clin Invest 2013 Sep 15;123(9):3967-82. Epub 2013 Aug 15.

Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.

Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.
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http://dx.doi.org/10.1172/JCI65570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754239PMC
September 2013

High endothelial venule blood vessels for tumor-infiltrating lymphocytes are associated with lymphotoxin β-producing dendritic cells in human breast cancer.

J Immunol 2013 Aug 3;191(4):2001-8. Epub 2013 Jul 3.

Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France.

Blood vessels and tumor angiogenesis are generally associated with tumor growth and poor clinical outcome of cancer patients. However, we recently discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis. These vessels, designated tumor high endothelial venules (HEVs), appear to facilitate tumor destruction by allowing high levels of lymphocyte infiltration into tumors. In this study, we investigated the mechanisms regulating HEV blood vessels in human breast cancer. We found that lymphotoxin β was overexpressed in tumors containing high densities of HEVs (HEV(high)) and correlated to DC-LAMP, a marker of mature DCs. DCs were the main producers of lymphotoxin β in freshly resected HEV(high) breast tumor samples, and the density of DC-LAMP(+) DCs clusters was strongly correlated with the density of tumor HEVs, T and B cell infiltration, and favorable clinical outcome in a retrospective cohort of 146 primary invasive breast cancer patients. Densities of tumor HEVs and DC-LAMP(+) DCs were strongly reduced during breast cancer progression from in situ carcinoma to invasive carcinoma, suggesting that loss of tumor HEVs is a critical step during breast cancer progression. Finally, an increase in the infiltration of regulatory T cells was observed in HEV(high) breast tumors, indicating that tumor HEVs can develop in the presence of regulatory T cells. Together, our results support a key role for DCs and DC-derived lymphotoxin in the formation of tumor HEVs. These findings are important because novel therapeutic strategies based on the modulation of tumor HEVs could have a major impact on clinical outcome of cancer patients.
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http://dx.doi.org/10.4049/jimmunol.1300872DOI Listing
August 2013