The Roles of Kidney-Resident ILC2 in Renal Inflammation and Fibrosis

Abstract

Innate lymphoid cells (ILCs) are a recently discovered lymphocyte population with high cytokine productive capacity. Type-2 ILCs (ILC2s) are the most studied, and they exert a rapid type-2 immune response to eliminate helminth infections. Massive and sustainable ILC2 activation induces allergic tissue inflammation, so it is important to maintain correct ILC2 activity for immune homeostasis. The ILC2-activating cytokine IL-33 is released from epithelial cells upon tissue damage, and it is upregulated in various kidney disease mouse models and in kidney disease patients. Various kidney diseases eventually lead to renal fibrosis, which is a common pathway leading to end-stage renal disease and is a chronic kidney disease symptom. The progression of renal fibrosis is affected by the innate immune system, including renal-resident ILC2s; however, the roles of ILC2s in renal fibrosis are not well understood. In this review, we summarize renal ILC2 function and characterization in various kidney diseases and highlight the known and potential contributions of ILC2s to kidney fibrosis.

Keywords: CKD - chronic kidney disease; IL-33; ILC2; ILCreg; renal fibrosis.

Figure 1

Potential functions in renal ILC2. ILC2 have protective functions in kidney, but exerts positively or negatively effects in dependent on the amount of renal IL-33. Upon kidney injury and disease, IL-33 released from vascular endothelial cells and/or tubular epithelial cells leads to activate renal-resident ILC2, and secreted type2 cytokines possibly affects in following events; (A) tissue repair by inducing M2 macrophages, (B) hypertension and cardiovascular disease through renin-angiotensin system, (C) renal anemia mediated by EPO, (D) renal fibrosis via the plasticity for TGF-β producing ILCreg.

Figure 2

ILC2 contribution for renal fibrosis. Renal fibrosis is partially induced by pro-fibrotic factors including TGF- β from M2 macrophages, Tregs, and ILCs, and fibroblasts accelerate trans-differentiation to myofibroblasts in renal stromal region. Activation of myofibroblast occurs excessive ECM deposition, leading to impair renal functions. Renal ILC2 possibly contribute to enhance fibrosis at following aspects of myofibroblast activation; (A) ILC2-ILCreg plasticity, (B) M2 macrophages differentiation, (C) direct effect by Areg production, (D) indirect effect via eosinophils induced by IL-5, (E) Effect of Areg to produce pro-fibrotic factors on tubular epithelial cells, vascular endothelial cells, fibroblasts and pericytes.