IL-10 Deficiency Research Articles

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung.

The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.

Meet the First Author.

HomeCirculation ResearchVol. 126, No. 3Meet the First Author Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Author Originally published30 Jan 2020https://doi.org/10.1161/RES.0000000000000324Circulation Research. 2020;126:296–297is related toFunctional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and AdipocytesAge-Associated Mitochondrial Dysfunction Accelerates AtherogenesisA Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyteis related toInterleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase EnrichmentDuration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific MortalityVascular Aging, Mitochondria, and Atherogenesis (p 298)Download figureDownload PowerPointDr Dan Tyrrell is a postdoctoral fellow in Dr Daniel Goldstein’s laboratory at the University of Michigan. He completed his PhD in Dr Anthony Molina’s laboratory in Integrative Physiology and Pharmacology at Wake Forest School of Medicine. Dan’s recent work demonstrates a positive feedback loop of increased IL-6 and mitochondrial dysfunction within the aging aorta that accelerates atherogenesis. His long-term goal is to determine how mitochondria and inflammation interact in multiple vascular beds with aging, and how these changes enhance disease. Dan enjoys running and biking when he isn’t spending time with his family (ie, chasing after his two young sons). He can be found on Twitter @dantyrr.IL-10 Deficiency Impairs EPC Exosome Function (p 315)Download figureDownload PowerPointDr Yujia Yue earned her BS in Medicine from Fudan University in China. She became interested in life sciences and basic biomedical research while earning her MD. She came to the US in 2014 and completed her PhD in May 2019 (mentor, Dr Raj Kishore) at the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, focusing on stem cell-derived exosome in cardiac regeneration. After earning her PhD, Yujia joined Merck as an Associate Scientist. She is interested in furthering her scientific pursuit of translational medicine and drug discovery and plans to continue her scientific career in industry.CRISPR Screen for Genes Affecting Insulin Resistance (p 330)Download figureDownload PowerPointDr Zhifen Chen is a postdoctoral fellow in Dr Chad Cowan’s group at the Harvard Stem Cell Institute, where her research focuses on functional genomics of polygenic traits, including insulin resistance and glucose levels. She earned her PhD from Technical University of Munich (TUM) in 2016 and her MS from Tsinghua University, Beijing, in 2012. She was mentored by Dr Karl-Ludwig Laugwitz, focussing on cardiac disease modelling using patient-induced pluripotent stem cell (iPSC)-derived cardiomyocytes, including a type of long QT syndrome and a case of familial dilated cardiomyopathy. The goal of her research is to identify unknown genes contributing to adipose insulin resistance and test their therapeutic potentials for obesity or type 2 diabetes and their related cardiometabolic comorbidities. Outside of the lab, she enjoys dancing, biking, and discussing life experiences and diverse fields of science. She plans to establish her own lab in the near future.Desmin and the Nucleus (p e10)Download figureDownload PowerPointJulie Heffler is a doctoral candidate at the University of Pennsylvania in the lab of Dr Ben Prosser. She began her career as an undergraduate at the University of Houston, where she earned her BS in Biochemistry. During her time at UH, she worked in the lab of Dr Kevin Morano at UT Health researching chaperones and protein misfolding. Currently, her research at UPenn has focused on the attachment of the cytoskeleton to the nucleus in adult cardiomyocytes and how these cells sense mechanical signals, continuing her long-held interest in cell sensing and signal transduction. She can be found on Twitter @julieheffler.Antibiotics and Risk of Mortality (p 364)Download figureDownload PowerPointDr Yoriko Heianza is a postdoctoral research fellow in the Department of Epidemiology at Tulane University. She earned her PhD in Medicine from the University of Tsukuba, Japan. She previously earned her BS from the Doshisha Women’s College of Liberal Arts, Kyoto, Japan, where she gained a broad knowledge of nutrition. She has been exploring genetic, metabolomic, diet/lifestyle factors in the development of obesity and cardiovascular disease in Dr Lu Qi’s Lab at Tulane University, with the support of an AHA Postdoctoral Fellowship. She has also received two awards for her research from the AHA. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesFunctional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and AdipocytesZhifen Chen, et al. Circulation Research. 2020;126:330-346Interleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase EnrichmentYujia Yue, et al. Circulation Research. 2020;126:315-329Age-Associated Mitochondrial Dysfunction Accelerates AtherogenesisDaniel J. Tyrrell, et al. Circulation Research. 2020;126:298-314A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the CardiomyocyteJulie Heffler, et al. Circulation Research. 2020;126:e10-e26Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific MortalityYoriko Heianza, et al. Circulation Research. 2020;126:364-373 January 31, 2020Vol 126, Issue 3 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000324PMID: 31999534 Originally publishedJanuary 30, 2020 PDF download Advertisement

Ischemic cardiomyopathy: blood monocytes and mediators of their differentiation

BACKGROUND: The three-year survival rate of patients with ischemic cardiomyopathy (ICMP) is 535 %; its pathogenesis is poorly understood. Violation of cytokine-dependent differentiation of monocytes/macrophages involved in atherogenesis may play an important role in the development of ICMP.
 AIMS: To characterize the disorders of monocytes subpopulation composition and mediators spectrum of blood in patients with coronary heart disease (CHD), associated with the development of ICMP.
 METHODS: A one-stage, clinical, controlled (case-control) study was conducted from February 2017 to December 2018. 45 patients with CHD (all men), who were in a cardiac surgery hospital, were examined before coronary bypass surgery: 19 people suffering from ICMP, and 26 people who do not suffer from ICMP, as well as 14 healthy men. In the blood of the examined individuals CD14++CD16-, CD14++CD16+, CD14+CD16++ and CD14+CD16- monocytes were determined with respect to all CD14-positive cells by flow cytometry, in blood plasma ― concentration of galectin 2 and 9, IL-4, IL-10, IFN-, M-CSF, HIF-1 by enzyme-linked immunosorbent assay (ELISA).
 RESULTS: The development of the ICMP accompanied by deficiency of HIF-1 and CD14+CD16++ monocytes (0.037 [0.020; 0.045] ng/ml, p = 0.019, and 5.05 [4.08; 6.58] %, p = 0.011) in combination with an excess of IL-10 (30.05 [24.75; 33.50] ng/ml, p = 0.042) in the blood. It is shown in blood of patients without ischemic cardiomyopathy the increase in the content of CD14++CD16+ cells and lack of CD14+CD16- monocytes (25.27 [15.78; 31.39] %, p = 0.038, and 2.68 [2.63; 4.09] %, p = 0.027) at normal concentration of IL-10 and HIF-1. In patients with CHD and ischemic cardiomyopathy and without ICMP in the blood the concentration of M-CSF and galectin-2 (2.00 [1.21; 3.24] pg/ml, p = 0.028, and 0.40 [0.12; 2.37] ng/ml, p = 0.004; 3.00 [1.90; 4.05] pg/ml, p = 0.003, and 3.20 [2.07; 4.00] ng/ml, p = 0.002, respectively) is reduced at normal content of galectin-9, and CD14++CD16- monocytes. IL-4 and IFN- in blood plasma are not determined (zero values).
 CONCLUSIONS: The development of ICMP is associated with excess of IL-10 and HIF-1 deficiency, which is accompanied by inhibition of CD14+CD16++ monocytes maturation.

RETRACTED: Two Cases of Interleukin-7–Deficient Generalized Verrucosis

We report 2 generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. Unlike the previous report in which IL-7 deficiency accompanied CD4 T lymphocytopenia, circulating CD4 T cells were not depleted in one of our patients, suggesting a GV pathogenesis other than poor T-cell development.

PREGNANCY, COMPLICATED BY PREECLAMPSIA: FETOPLACENTAL COMPLEX IMMUNE DEADAPTATION AND HISTOSTRUCTURAL FEATURES

The aim: to study and compare the features of the interleukins levels and morphological changes of placenta at various stages of preeclampsia. Materials and methods: 109 pregnant women with preeclampsia of varying severity (study group) and 30 pregnant women with uncomplicated pregnancy (control group) were examined. Immunohistochemical method, proinflammatory interleukins levels, morphological and morphometric analysis of peripheral and central placental areas biopsies on the optical and electron-microscopic level have been used. Results: Morphofunctional changes in the placenta in case of preeclampsia and the increase in the expression level of the transforming growth factor have a series of regular stages from the formation, strain and disruption of adaptive mechanisms with more pronounced signs of morphological immaturity of parenchymal and stromal elements of the placenta, especially in the area of syncytiotrophoblast and spiral vessels. The degree of clinical manifestation of preeclampsia has a correlation relationship with IL-10 deficiency and with the increase in TNF-α, stimulation of macrophage-protein production that contributes to the change in the ratio of Thl / Th2, which are antagonists and inhibit each other's development. Conclusions: The severity of the preeclampsia course correlates with the state of morphofunctional changes in the placenta and changes in the ratio of the pro- and anti-inflammatory interleukins.

Abstract B02: Tissue-specific innate lymphoid cells are novel targets for pancreatic cancer immunotherapy

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the classic cold tumor, with few tumor-infiltrating activated CD8+ T cells, a major barrier to immunotherapy. Strategies to convert cold PDACs to hot can enable more effective immunotherapies. To identify targets that can convert cold PDACs to hot, we compared a large cohort of rare long-term PDAC survivors with hot tumors to short-term survivors with cold tumors. Surprisingly, hot PDACs were enriched not only in activated CD8+ T cells, but also in group-2 innate lymphoid cells (ILC2s), a class of largely tissue-resident, cytokine-producing innate lymphocyte that potentiates T cell immunity in local tissues. We identified that tumor ILC2s (TILC2s) infiltrate human and mouse PDACs, and TILC2 frequency and tumor expression of the ILC2-activating ligand interleukin (IL)-33 positively correlate with tumor immune cytolytic activity, and long-term patient survival. Using PDAC mouse models, we discovered that the IL33-ILC2 axis activates pancreatic tissue-specific antitumor T-cell immunity. Host IL33 deficiency attenuated TILC2 expansion and CD8+ T-cell activation, accelerating tumor growth in orthotopic PDACs but not heterotopic skin implanted PDACs where TILC2s lack the IL33 receptor. Acute ILC2 depletion partially phenocopied the tissue-specific phenotype of IL33 deficiency, with impaired rejection of immunogenic orthotopic but not heterotopic skin PDACs. Treatment with recombinant IL33 (rIL33), but not with the ILC1-activating ligand rIL18, increased TILC2 frequencies, activated CD8+ T cells, and abrogated orthotopic but not heterotopic PDAC establishment in >70% of mice. Taken together, these studies identify ILC2s as novel anticancer immune cells for PDAC immunotherapy. Strategies to activate tissue-specific ILC2s may be a promising immunotherapeutic approach for PDAC. Citation Format: Joanne Leung, Luis A Rojas, Jennifer Ruan, Julia Zhao, Billel Gasmi, Zachary Sethna, Anita Ramnarain, Umesh Bhanot, Gokce Askan, Murali Gururajan, Ela Elyada, Youngkyu Park, David A. Tuveson, Mithat Gonen, Steven D. Leach, Jedd D. Wolchok, Ronald P. DeMatteo, Taha Merghoub, Vinod P. Balachandran, John Alec Moral. Tissue-specific innate lymphoid cells are novel targets for pancreatic cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B02.

Evolutionary transition from degenerate to nonredundant cytokine signaling networks supporting intrathymic T cell development

In mammals, T cell development critically depends on the IL-7 cytokine signaling pathway. Here we describe the identification of the zebrafish ortholog of mammalian IL-7 based on chromosomal localization, deduced protein sequence, and expression patterns. To examine the biological role of il7 in teleosts, we generated an il7 allele lacking most of its coding exons using CRISPR/Cas9-based mutagenesis. il7-deficient animals are viable and exhibit no obvious signs of immune disorder. With respect to intrathymic T cell development, il7 deficiency is associated with only a mild reduction of thymocyte numbers, contrasting with a more pronounced impairment of T cell development in il7r-deficient fish. Genetic interaction studies between il7 and il7r mutants, and il7 and crlf2(tslpr) mutants suggest the contribution of additional, as-yet unidentified cytokines to intrathymic T cell development. Such activities were also ascertained for other cytokines, such as il2 and il15, collectively indicating that in contrast to the situation in mammals, T cell development in the thymus of teleosts is driven by a degenerate multicomponent network of γc cytokines; this explains why deficiencies of single components have little detrimental effect. In contrast, the dependence on a single cytokine in the mammalian thymus has catastrophic consequences in cases of congenital deficiencies in genes affecting the IL-7 signaling pathway. We speculate that the transition from a degenerate to a nonredundant cytokine network supporting intrathymic T cell development emerged as a consequence of repurposing evolutionarily ancient constitutive cytokine pathways for regulatory functions in the mammalian peripheral immune system.

IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment

BackgroundInterleukin-33 (IL-33) belongs to the IL-1 cytokine family and resides in the nuclei of various cell types. In the neural retina, IL-33 is predominately expressed in Müller cells although its role in health and disease is ill-defined. Müller cell gliosis is a critical response during the acute phase of retinal detachment (RD), and in this study, we investigated if IL-33 was modulatory in the inflammatory and neurodegenerative pathology which is characteristic of this important clinical condition.MethodsRD was induced by subretinal injection of sodium hyaluronate into C57BL/6 J (WT) and IL-33−/− mice and confirmed by fundus imaging and optical coherence tomography (OCT). The expression of inflammatory cytokines, complement components and growth factors was examined by RT-PCR. Retinal neurodegeneration, Müller cell activation and immune cell infiltration were assessed using immunohistochemistry. The expression of inflammatory cytokines in primary Müller cells and bone marrow-derived macrophages (BM-DMs) was assessed by RT-PCR and Cytometric Bead Array.ResultsRD persisted for at least 28 days after the injection of sodium hyaluronate, accompanied by significant cone photoreceptor degeneration. The mRNA levels of CCL2, C1ra, C1s, IL-18, IL-1β, TNFα, IL-33 and glial fibrillary acidic protein (GFAP) were significantly increased at day 1 post-RD, reduced gradually and, with the exception of GFAP and C1ra, returned to the basal levels by day 28 in WT mice. In IL-33−/− mice, RD induced an exacerbated inflammatory response with significantly higher levels of CCL2, IL-1β and GFAP when compared to WT. Sustained GFAP activation and immune cell infiltration was detected at day 28 post-RD in IL-33−/− mice. Electroretinography revealed a lower A-wave amplitude at day 28 post-RD in IL-33−/− mice compared to that in WT RD mice. IL-33−/− mice subjected to RD also had significantly more severe cone photoreceptor degeneration compared to WT counterparts. Surprisingly, Müller cells from IL-33−/− mice expressed significantly lower levels of CCL2 and IL-6 compared with those from WT mice, particularly under hypoxic conditions, whereas IL-33−/− bone marrow-derived macrophages expressed higher levels of inducible nitric oxide synthase, TNFα, IL-1β and CCL2 after LPS + IFNγ stimulation compared to WT macrophages.ConclusionIL-33 deficiency enhanced retinal degeneration and gliosis following RD which was related to sustained subretinal inflammation from infiltrating macrophages. IL-33 may provide a previously unrecognised protective response by negatively regulating macrophage activation following retinal detachment.

Stability and Maintenance of Foxp3+ Treg Cells in Non-lymphoid Microenvironments.

Foxp3+ Treg cells are indispensable for maintaining self-tolerance in secondary lymphoid organs (SLOs). However, Treg cells are also recruited to non-lymphoid tissues (NLTs) during inflammation. Recent advances in the understanding of Treg cell biology provided us with molecular mechanisms—both transcriptional and epigenetic—that enable Treg cells to retain their identity in an inflammatory milieu that is per se hostile to sustained expression of high levels of Foxp3. While Treg cells are recruited to sites of inflammation in order to resolve inflammation and re-establish appropriate organ function, it is increasingly recognized that a series of inflammatory (but also non-inflammatory) perturbations of organ function lead to the constitution of relatively long lived populations of Treg cells in NLTs. NLT Treg cells are heterogeneous according to their respective site of residence and it will be an important goal of future investigations to determine how these NLT Treg cells are maintained, e.g., what the role of antigen recognition by NLT Treg cells is and which growth factors are responsible for their self-renewal in the relative deficiency of IL-2. Finally, it is an open question what functions NLT Treg cells have besides their role in maintaining immunologic tolerance. In this review, we will highlight and summarize major ideas on the biology of NLT Treg cells (in the central nervous system but also at other peripheral sites) during inflammation and in steady state.

Associations of Interleukin-5 With Plaque Development and Cardiovascular Events

Experimental studies have suggested an atheroprotective role of interleukin (IL)-5 through the stimulation of natural immunoglobulin M antibody expression. In the present study we show that there are no associations between baseline levels of IL-5 and risk for development of coronary events or stroke during a 15.7 ± 6.3 years follow-up of 696 subjects randomly sampled from the Malmö Diet and Cancer study. However, presence of a plaque at the carotid bifurcation was associated with lower IL-5 and IL-5 deficiency resulted in increased plaque development at sites of oscillatory blood flow in Apoe -/- mice suggesting a protective role for IL-5 in plaque development.

IL-6 deficiency attenuates p53 protein accumulation in aged male\xa0mouse hippocampus

Our earlier studies demonstrated slower age-related memory decline in IL-6-deficient than in control mice. Therefore, in the present study we evaluated the effect of IL-6 deficiency and aging on expression of p53, connected with accumulation of age-related cellular damages, in hippocampus of 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and wild type control (WT) mice. The accumulation of p53 protein in hippocampus of aged IL-6KO mice was significantly lower than in aged WT ones, while p53 mRNA level was significantly higher in IL-6-deficient mice, what indicates that the effect was independent on p53 transcription. Presence of few apoptotic cells in hippocampal dentate gyrus and lack of changes in levels of pro-apoptotic Bax, antiapoptotic Bcl-2, as well as in p21 protein in aged animals of both genotypes, points to low transcriptional activity of p53, especially in aged WT mice. Because the amount of p53 protein did not correlate with the level of Mdm2 protein, its main negative regulator, other than Mdm2-dependent mechanism was involved in p53 build-up. Significantly higher mRNA levels of autophagy-associated genes: Pten, Tsc2, and Dram1 in IL-6KO mice, in conjunction with significantly lower amount of Bcl-2 protein in 4-month-old IL-6KO mice, suggests that lack of IL-6/STAT3/Bcl-2 signaling could account for better autophagy performance in these mice, preventing excessive accumulation of proteins. Taken together, attenuated p53 protein build-up, absence of enhanced apoptosis, and transcriptional up-regulation of autophagy-associated genes imply that IL-6 deficiency may protect hippocampus from age-related accumulation of cellular damages.

Loss of IL-10 Promotes Differentiation of Microglia to a M1 Phenotype.

Microglia represent the primary resident immune cells of the central nervous system (CNS) and modulate local immune responses. Depending on their physiological functions, microglia can be classified into pro- (M1) and anti-inflammatory (M2) phenotype. Interleukin (IL)-10 is an important modulator of neuronal homeostasis, with anti-inflammatory and neuroprotective functions, and can be released by microglia. Here, we investigated how IL-10 deficiency affected the M1/2 polarization of primary microglia upon lipopolysaccharide (LPS) stimulation in vitro. Microglia phenotypes were analyzed via flow cytometry. Cytokine and chemokine secretion were examined by ELISA and bead-based multiplex LEGENDplexTM. Our results showed that genetic depletion of IL-10 led to elevated M1 like phenotype (CD86+ CD206−) under pro-inflammatory conditions associated with increased frequency of IL-6+, TNF-α+ cells and enhanced release of several pro-inflammatory chemokines. Absence of IL-10 led to an attenuated M2 like phenotype (CD86− CD206+) and a reduced secretion of TGF-β1 upon LPS stimulation. In conclusion, IL-10 deficiency may promote the polarization of microglia into M1-prone phenotype under pro-inflammatory conditions.

Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG

Background & AimsToll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood.MethodsALD-associated liver injury were induced in TLR2 knockout (TLR2–/–), TLR3–/–, TLR2–/– bone marrow transplanted (BMT), TLR3–/– BMT, IL-10–/– mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD.ResultsWe identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG’s actions.ConclusionsAltogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.

IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development.

IL-33 is an IL-1 family member protein that is a potent driver of inflammatory responses in both allergic and nonallergic disease. This proinflammatory effect is mediated primarily by extracellular release of IL-33 from stromal cells and binding of the C-terminal domain of IL-33 to its receptor ST2 on targets such as CD4+ Th2 cells, ILC2, and mast cells. Notably, IL-33 has a distinct N-terminal domain that mediates nuclear localization and chromatin binding. However, a defined in vivo cell-intrinsic role for IL-33 has not been established. We identified IL-33 expression in the nucleus of progenitor B (pro-B) and large precursor B cells in the bone marrow, an expression pattern unique to B cells among developing lymphocytes. The IL-33 receptor ST2 was not expressed within the developing B cell lineage at either the transcript or protein level. RNA sequencing analysis of wild-type and IL-33-deficient pro-B and large precursor B cells revealed a unique, IL-33-dependent transcriptional profile wherein IL-33 deficiency led to an increase in E2F targets, cell cycle genes, and DNA replication and a decrease in the p53 pathway. Using mixed bone marrow chimeric mice, we demonstrated that IL-33 deficiency resulted in an increased frequency of developing B cells via a cell-intrinsic mechanism starting at the pro-B cell stage paralleling IL-33 expression. Finally, IL-33 was detectable during early B cell development in humans and IL33 mRNA expression was decreased in B cell chronic lymphocytic leukemia samples compared with healthy controls. Collectively, these data establish a cell-intrinsic, ST2-independent role for IL-33 in early B cell development.

Interleukin-10 Promotes Porcine Circovirus Type 2 Persistent Infection in Mice and Aggravates the Tissue Lesions by Suppression of T Cell Infiltration

Interleukin (IL)-10, as a key anti-inflammatory cytokine, increases during porcine circovirus type 2 (PCV2) infection, but the role of IL-10 in the process remains to be defined. In the present study, using an IL-10 deficient mice model, we found that IL-10 deficiency prevented the reduction of splenic lymphocytes (CD45+ cells) induced by PCV2 and promoted CD4+ and CD8+ T cell infiltration in lungs through inducting more T cell chemokines (CCL3, CXCL9, and CXCL10). Simultaneously, PCV2 infection induced a significant increase of pro-inflammatory cytokines and PCV2-specific antibodies in IL-10 deficient mice than in wild-type mice, resulting in a lower viral load in lung and a milder lung lesion in IL-10 deficient mice relative to wild-type mice. Moreover, the amounts of pulmonary CD4+ and CD8+ T cells were all inversely correlated with the lung lesions, as well as the viral load of PCV2. These results demonstrate that PCV2 infection employs IL-10 to block the transfer of T cells to the lungs of mice, and IL-10 attenuates the production of pro-inflammatory cytokines and PCV2-specific antibodies. The lack of T cell infiltration, pro-inflammatory cytokines, and PCV2-specific antibodies promote PCV2 replication, leading to a more severe lung lesion in mice.

IL-17 Inversely Correlated with IL-10 via the STAT3 Gene in Pneumocystis-Infected Mice.

Background Pneumocystis pneumonia (PCP) remains a common opportunistic infection in immunosuppressed individuals. Current studies showed that multiple immune cells and cytokines took part in the host defense against Pneumocystis (PC). However, the roles of IL-17 and IL-10 in the development of PCP have not been elucidated. Methods IL-10 and IL-17 levels in serum from PCP mice were detected via ELISA. The percentages of B10 cells, IL-10+ macrophages, and IL-10+ T cells in the lung from IL-17–/– PCP mice and Th17 cells and IL-17+γδT cells in IL-10–/– PCP mice were examined via flow cytometry. Also, antibody neutralization examination was also performed to elucidate the relationship of IL-17 and IL-10 in the PCP model. Results We noted the increase of IL-17 and IL-10 levels in serum from mice infected with Pneumocystis. Furthermore, deficiency of IL-17 or IL-10 could lead to the delayed clearance of Pneumocystis and more severed lung damage. Our data also demonstrated that IL-17 deficiency enhanced the serum IL-10 level and the percentages of B10 cells, IL-10+ macrophages, and IL-10+ T cells in the lung from PCP mice. Interestingly, we also noted an increase of the IL-17 level in serum and Th17 cell and IL-17+γδT cell percentages in the lung from IL-10–/– PCP mice. Using antibody neutralization experiments, we found that the STAT3 gene might play a critical role in the interplay of IL-17 and IL-10 in PCP. Conclusion Taken together, our results demonstrated that IL-17 and IL-10 could play the protective roles in the progression of PCP and the inverse correlation of them might be mediated by STAT3.

Evaluation of serum interleukin 17 and zinc levels in recalcitrant viral wart.

Warts are benign epithelial proliferations of the skin and mucosa caused by infection with HPV. Low IL-17 levels may contribute in occurrence, maintenance, severity, and recurrence of different types of cutaneous wart that depend mainly on the cell-mediated immunity defect. In a majority of the patients, zinc deficiency was associated with persistent, progressive, or recurrent viral warts. A careful dose of oral zinc sulfate may be helpful in the management of such patients. Zn deficiency negatively affects the Th17 cells. IL 6 induced STAT3 activation during chronic inflammation and Th17 development suppressed by Zn via attenuating this activation critically controls Th17-cell development. To evaluate the role of interleukin 17 and zinc in recalcitrant warts. All studied patients were subjected to history taking and dermatological examination. The evaluation of serum IL-17 level was done by ELISA in 25 recalcitrant wart patients and 25 wart patients. The measurement of serum zinc level was determined by colorimetric methods, using Au 480 Beckman coulter chemistry analyzer. The results revealed a significant decrease in serum IL-17 and zinc levels in recalcitrant wart patients. Both IL-17 and zinc deficiency have a role in the pathogenesis of recalcitrant warts through the imbalance of immune system and deficiency of immune cells. There is no significant correlation between serum levels of IL-17 and zinc, suggesting that they have different mechanisms in affecting the immune system.

IL-17A-Producing γδT Cells Inhibit the Formation of Malignant Pleural Effusions.

γδT cells are an important source of IL-17A and play an anti- or protumor role depending on the surrounding microenvironment. The precise role of γδT cells in the development of malignant pleural effusions (MPE) remains unknown. Using flow cytometry, we analyzed the distribution and differentiation of γδT cells in wild-type (WT) and IL-10-∕- mice. We carefully elucidated the influence of γδT cells on the formation of MPE by depleting γδT cells from WT, IL-10-∕-, and IL-17a-∕- mice. The distribution of γδT17 cells in human MPE and peripheral blood was also determined. Our data showed that both γδT cells and IL-17A-producing γδT (γδT17) cells accumulated in murine MPE, and IL-10 deficiency enhanced their accumulation. γδT cells were the main source of IL-17A in MPE for both WT and IL-10-∕- mice. IL-10 inhibited the chemotactic response of γδT cells to MPE and the proliferation of these cells. IL-10 suppressed γδT cell secretion of IL-17A via RORγt. The ablation of γδT cells accelerated MPE accumulation in both WT and IL-10-∕- mice, but it did not influence MPE accumulation in IL-17a-∕- mice. Patients with higher frequencies of γδT17 cells had significantly longer survival times than patients with lower frequencies of γδT17 cells. Taken together, our data demonstrate that γδT17 cells play an inhibitory role in the progression of MPE, and the accumulation of γδT17 cells in MPE is suppressed by IL-10.

Deficient IL-2 Produced by Activated CD56+ T Cells Contributes to Impaired NK Cell-Mediated ADCC Function in Chronic HIV-1 Infection.

Background: Antibody-dependent cellular cytotoxicity (ADCC), which mainly mediated by natural killer (NK) cells, may play a critical role in human immunodeficiency virus type-1 (HIV-1) disease progression. However, the potential mechanisms that affecting NK-mediated ADCC response are still not well-elucidated.Methods: Antigen-antibody complex model of Ab-opsonized P815 cells was adopted to induce a typical non-specific ADCC response. The capacities of HIV-1 specific NK-ADCC were measured by using the combination model of gp120 protein and plasma of HIV-1 elite controllers. The levels of plasma cytokine were measured by ELISA. Anti-IL-2 blocking antibody was used to analyze the impact of activated CD56+ T cells on NK-ADCC response.Results: IL-2, IL-15, IFN-α, and IFN-β could effectively enhance the non-specific and HIV-1-specific NK-ADCC responses. Compared with healthy controls, HIV-1-infected patients showed decreased plasma IL-2 levels, while no differences of plasma IFN-α, IL-15, and IFN-β were presented. IL-2 production was detected from CD56+ T cells activated through antibody-dependent manner. The capability of NK-ADCC could be weakened by blocking IL-2 secretion from activated CD56+ T cells. Although no difference of frequencies of CD56+ T cells was found between HIV-1-infected patients and healthy controls, deficient IL-2 secretion from activated CD56+ T were found in chronic HIV-1 infection.Conclusions: The impaired ability of activated CD56+ T cells to secreting IL-2 might contribute to the attenuated NK cell-mediated ADCC function in HIV-1 infection.

Attenuation of Allergen-, IL-13-, and TGF-α-induced Lung Fibrosis after the Treatment of rIL-15 in Mice.

Endogenous IL-15 deficiency promotes lung fibrosis; therefore, we examined the effect of induced IL-15 in restricting the progression of lung fibrosis. Our objective in this work was to establish a novel therapeutic molecule for pulmonary fibrosis. Western blot, qPCR, and ELISA were performed on the lung tissues of IL-15-deficient mice, and recombinant IL-15 (rIL-15)-treated CC10-IL-13 and CC10-TGF-α mice, and allergen-challenged CC10-IL-15 mice were examined to establish the antifibrotic effect of IL-15 in lung fibrosis. We show that endogenous IL-15 deficiency induces baseline profibrotic cytokine and collagen accumulation in the lung, and pharmacological delivery of rIL-15 downregulates Aspergillus antigen-induced lung collagen, the profibrotic cytokines IL-13 and TGF-β1, and α-SMA+ and FSP1+ cells in mice. To confirm that overexpression of IL-15 diminishes pulmonary fibrosis, we generated CC10-rtTA-tetO7-IL-15 transgenic mice and challenged them with Aspergillus antigen. Aspergillus antigen-challenged, doxycycline (DOX)-treated CC10-IL-15 transgenic mice exhibited decreased collagen accumulation, profibrotic cytokine (IL-13 and TGF-β1) expression, and α-SMA+ and FSP1+ cells compared with IL-15-overexpressing mice not treated with DOX. Additionally, to establish that the antifibrotic effect of IL-15 is not limited to allergen-induced fibrosis, we showed that rIL-15 or IL-15 agonist treatment restricted pulmonary fibrosis even in CC10-IL-13 and CC10-TGF-α mice. Mechanistically, we show that T-helper cell type 17 suppressor IL-15-responsive RORγ+ T regulatory cells are induced in DOX-treated, allergen-challenged IL-15-overexpressing mice, which may be a novel pathway for restricting progression of pulmonary fibrosis. Taken together, our data establishes antifibrotic activity of IL-15 that might be a novel therapeutic molecule to combat the development of pulmonary fibrosis.