Interleukin-22 From Type 3 Innate Lymphoid Cells Aggravates Lupus Nephritis by Promoting Macrophage Infiltration in Lupus-Prone Mice.

Lingzhen Hu,Liheng Chen,Jingyi Hu,Yi Zhang,Xuyan Yang,Qingqing Wang

doi:10.3389/fimmu.2021.584414

Lingzhen Hu, Liheng Chen + Show 4 more

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https://doi.org/10.3389/fimmu.2021.584414

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Abstract

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Our previous studies demonstrated increased serum and renal Interleukin (IL)-22 in LN patients and MRL/lpr mice. This study investigated the role of IL-22 and its mechanism in LN. Here, we found that IL-22 was mainly produced by type 3 innate lymphoid cells (ILC3) in kidney of MRL/lpr mice. The systemic illness and local renal lesion were significantly alleviated in IL-22 or IL-22R gene knockout (KO) mice (IL-22 KO or IL-22R KO MRL/lpr mice) than control mice (MRL/lpr mice). IL-22 KO or IL-22R KO MRL/lpr mice had significantly slighter infiltration of macrophage in kidney than MRL/lpr mice. Consistently, by RNA-Seq, the expression of (CC motif) ligand 2 (CCL2) and (CXC motif) ligand 10 (CXCL10) was decreased in kidney of KO mice compared with control mice. By immunoblotting, significantly increased levels of STAT3 phosphorylation were found in the kidney of control mice compared to KO mice. In vitro, primary kidney epithelial cells from control mouse stimulated with recombinant IL-22 (rIL-22) expressed higher levels of CCL2, CXCL10, and phosphorylated STAT3. At the same time, when primary kidney epithelial cells were treated with rIL-22, transwell assay demonstrated their supernatant recruited more macrophages. In human kidney epithelial cell line (HK2) cells, when treated with rIL-22, we observed similar results with primary mouse kidney epithelial cells. Moreover, when cells were stimulated with rIL-22 following pre-treatment with STAT3 pathway inhibitor, the expression of CCL2 and CXCL10 were significantly reversed. Our findings demonstrate that IL-22 binding to IL-22R in kidney epithelial cells activated the STAT3 signaling pathway, enhanced the chemokine secretion and then promoted macrophage infiltration to the kidney of MRL/lpr mice, thus aggravated LN in lupus-prone mice. These findings indicate that IL-22 may play a pathogenic role in LN and may provide a promising novel therapeutic target for LN.

Highlights

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, resulting from auto-immune dysfunction, and presenting with immune complex-mediated lesions in diverse organ [1]
We found that IL-22 was mainly secreted by ILC3 in MRL/lpr mice, and deleting IL-22 or IL-22 receptor (IL-22R) decreased the systemic illness and lupus nephritis severity in lupus-prone mice
We found that deleting IL-22 or IL-22R downregulated CCL2 and CXCL10 expression, and decreased the filtration of macrophage into the kidney of lupus-prone mice

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, resulting from auto-immune dysfunction, and presenting with immune complex-mediated lesions in diverse organ [1]. Despite the improvement of therapeutic approaches in recent years, 12-month complete renal response rates are only 10%–40% [3], and for all LN patients, the cumulative incidence of end-stage renal disease (ESRD) at 10 years after the diagnosis of LN was 10.1% [4]. We previously found that IL-22 was increased in serum and renal tissue of both LN patients and MRL/lpr mice [11], and that elevated urinary IL-22 binding protein(IL-22BP) in LN patients were associated active renal disease [12]. Our further experiments demonstrated that MRL/ lpr mice treated with anti-IL-22 monoclonal antibody (mAb) had substantial improvement of renal function and less renal injury [11]

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