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

Riedel, Jan-Hendrik; Becker, Mies J.; Kopp, Kerstin; Düster, Mathis; Brix, Silke R.; Meyer-Schwesinger, Catherine; Kluth, Luis; Gnirck, Ann-Christin; Attar, Madena; Krohn, Sonja; Fehse, Boris; Stahl, Rolf A.K.; Panzer, Ulf; Turner, Jan-Eric

doi:10.1681/asn.2016080877

Cited by 92 publications

(128 citation statements)

References 50 publications

(69 reference statements)

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“…1B). In other types of innate lymphocytes, IL‐33 can stimulate IL‐5 and IL‐13 expression 19 . In contrast, IL‐33 alone or in combination with IL‐12 had no measurable effect on expression of IL5 or IL13 expression by human NK cells (Fig.…”

Section: Resultsmentioning

confidence: 95%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

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Section: Resultsmentioning

confidence: 95%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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“…A and B). We recently described ILC2s to be the major ILC subtype residing in the kidney of C57BL/6 and BALB/c mice . Similarly, in MRL control mice, as well as in and young and in diseased MRL‐ lpr mice, almost 80% of total ILCs were characterized as Lin − CD127 + CD25 hi GATA3 + ILC2s.…”

Section: Resultsmentioning

confidence: 97%

T cell‐derived IFN‐γ downregulates protective group 2 innate lymphoid cells in murine lupus erythematosus

et al. 2018

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Innate lymphoid cells (ILCs) are important regulators of the immune response and play a crucial role in the restoration of tissue homeostasis after injury. GATA-3 IL-13- and IL-5-producing group 2 innate lymphoid cells (ILC2s) have been shown to promote tissue repair in barrier organs, but despite extensive research on ILCs in the recent years, their potential role in autoimmune diseases is still incompletely understood. In the present study, we investigate the role of ILC2s in the MRL/MpJ-Fas (MRL-lpr) mouse model for severe organ manifestation of systemic lupus erythematosus (SLE). We show that in these MRL-lpr mice, progression of lupus nephritis is accompanied with a reduction of ILC2 abundance in the inflamed renal tissue. Proliferation/survival and cytokine production of kidney-residing ILC2s was suppressed by IFN-γ and, to a lesser extent, by IL-27 which were produced by activated T cells and myeloid cells in the nephritic kidney, respectively. Most importantly, restoration of ILC2 numbers by IL-33-mediated expansion ameliorated lupus nephritis and prevented mortality in MRL-lpr mice. In summary, we show here that development of SLE-like kidney inflammation leads to a downregulation of the renal ILC2 response and identify an ILC2-expanding therapy as a promising treatment approach for autoimmune diseases.

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“…IL‐33 induced partial protection against the typical features of doxorubicin‐induced nephropathy such as tubular inflammation and fibrotic‐like remodeling . It was demonstrated that these effects occur independently of adaptive immunity using mice deficient in T and B cells ( Rag2 −/− ), and mice deficient in T, B and ILCs ( Rag2 −/− Il2rcg −/− ) . However, it is also possible that non‐ILC, ST2 expressing cells such as basophils, eosinophils and mast cells may have important roles in protection against renal insult .…”

Section: Ilc2s As a Potential Cellular Therapy In Renal Injurymentioning

confidence: 99%

Emerging therapeutic potential of group 2 innate lymphoid cells in acute kidney injury

Cameron

Jiang

Loering

et al. 2019

The Journal of Pathology

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Acute kidney injury (AKI) remains a global challenge and, despite the availability of dialysis and transplantation, can be fatal. Those that survive an AKI are at increased risk of developing chronic kidney disease and end stage renal failure. Understanding the fundamental mechanisms underpinning the pathophysiology of AKI is critical for developing novel strategies for diagnosis and treatment. A growing body of evidence indicates that amplifying type 2 immunity may have therapeutic potential in kidney injury and disease. Of particular interest are the recently described subset of innate immune cells, termed group 2 innate lymphoid cells (ILCs). Group 2 ILCs are crucial tissue‐resident immune cells that maintain homeostasis and regulate tissue repair at multiple organ sites, including the kidney. They are critical mediators of type 2 immune responses following infection and injury. The existing literature suggests that activation of group 2 ILCs and production of a local type 2 immune milieu is protective against renal injury and associated pathology. In this review, we describe the emerging role for group 2 ILCs in renal homeostasis and repair. We provide an in‐depth discussion of the most recent literature that use preclinical models of AKI and assess the therapeutic effect of modulating group 2 ILC function. We debate the potential for targeting these cells as novel cellular therapies in AKI and discuss the implications for future studies and translation. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

Cited by 92 publications

References 50 publications

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

T cell‐derived IFN‐γ downregulates protective group 2 innate lymphoid cells in murine lupus erythematosus

Emerging therapeutic potential of group 2 innate lymphoid cells in acute kidney injury

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