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IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis.

ABSTRACT: Innate lymphoid cells (ILCs) have an important role in the immune system's response to different forms of infectious and noninfectious pathologies. In particular, IL-5- and IL-13-producing type 2 ILCs (ILC2s) have been implicated in repair mechanisms that restore tissue integrity after injury. However, the presence of renal ILCs in humans has not been reported. In this study, we show that ILC populations are present in the healthy human kidney. A detailed characterization of kidney-residing ILC populations revealed that IL-33 receptor-positive ILC2s are a major ILC subtype in the kidney of humans and mice. Short-term IL-33 treatment in mice led to sustained expansion of IL-33 receptor-positive kidney ILC2s and ameliorated adriamycin-induced glomerulosclerosis. Furthermore, the expansion of ILC2s modulated the inflammatory response in the diseased kidney in favor of an anti-inflammatory milieu with a reduction of pathogenic myeloid cell infiltration and a marked accumulation of eosinophils that was required for tissue protection. In summary, kidney-residing ILC2s can be effectively expanded in the mouse kidney by IL-33 treatment and are central regulators of renal repair mechanisms. The presence of ILC2s in the human kidney tissue identifies these cells as attractive therapeutic targets for CKD in humans.

SUBMITTER: Riedel JH

PROVIDER: S-EPMC5491284 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis.

Riedel Jan-Hendrik JH Becker Martina M Kopp Kerstin K Düster Mathis M Brix Silke R SR Meyer-Schwesinger Catherine C Kluth Luis A LA Gnirck Ann-Christin AC Attar Madena M Krohn Sonja S Fehse Boris B Stahl Rolf A K RAK Panzer Ulf U Turner Jan-Eric JE

Journal of the American Society of Nephrology : JASN 20170202 7

Innate lymphoid cells (ILCs) have an important role in the immune system's response to different forms of infectious and noninfectious pathologies. In particular, IL-5- and IL-13-producing type 2 ILCs (ILC2s) have been implicated in repair mechanisms that restore tissue integrity after injury. However, the presence of renal ILCs in humans has not been reported. In this study, we show that ILC populations are present in the healthy human kidney. A detailed characterization of kidney-residing ILC ...[more]

PMID: 28154198

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Project description:Rationale: The major cause of heart failure is myocardium death consequent to detrimental cardiac remodeling and fibrosis following myocardial infarction. The cardiac protective cytokine interleukin (IL)-33, which signals by ST2 receptor binding, is associated with group 2 innate lymphoid cell (ILC2) activation and regulates tissue homeostasis and repair following tissue injury in various tissues. However, the distribution and role of IL-33-responsive ILC2s in cardiac fibrosis remain unclear. In this study, we elucidated the roles of IL-33-responsive cardiac-resident ILC2s and IL-33-mediated immunomodulatory functions in cardiac fibrosis. Methods: We examined the distribution of cardiac ILC2s by using flow cytometry. The roles of IL-33-mediated ILC2 expansion in cardiac fibrosis was evaluated in the mouse model of catecholamine-induced cardiac fibrosis. ILC-deficient Rag2‒/‒IL2Rγc‒/‒ mice were implemented to determine the contribution of endogenous ILC in the progression of cardiac fibrosis. Histopathological assessments, speckle tracking echocardiography, and transcriptome profile analysis were performed to determine the effects of IL-33-mediated cardiac protective functions. Results: We identified the resident cardiac ILC2s, which share similar cell surface marker and transcriptional factor expression characteristics as peripheral blood and lung tissue ILC2s. IL-33 treatment induced ILC2 expansion via ST2. In vivo, ILC-deficient Rag2‒/‒IL2Rγc‒/‒ mice developed exacerbated cardiac fibrosis following catecholamine-induced stress cardiac injury. IL-33 treatment expanded cardiac ILC2s and revealed protective effects against cardiac tissue damage with reduced cardiomyocyte death, immune cell infiltration, tissue fibrosis, and improved myocardial function. Transcriptome analysis revealed that IL-33 attenuated extracellular matrix synthesis- and fibroblast activation-associated gene expressions. IL13-knockout or epidermal growth factor receptor (EGFR) inhibition abolished IL-33-mediated cardiac protective function, confirming IL-13 and EGFR signaling as crucial for IL-33-mediated cardioprotective responses. Moreover, ILC2-produced BMP-7 served as a novel anti-fibrotic factor to inhibit TGF-β1-induced cardiac fibroblast activation. Conclusion: Our findings indicate the presence of IL-33-responsive ILC2s in cardiac tissue and that IL-33-mediated ILC2 expansion affords optimal cardioprotective function via ILC2-derived factors. IL-33-mediated immunomodulation is thus a promising strategy to promote tissue repair and alleviate cardiac fibrosis following acute cardiac injury.

Dataset Information

IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis.

Publications

IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis.

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