The Protective Role of Integrin a4ß7 and Amphiregulin-Expressing Innate Lymphoid Cells in Lupus Nephritis
Type-2 innate lymphoid cells (ILC2s) have emerged as key immune-response regulators in renal-inflammatory diseases such as lupus nephritis. However, the adhesion and migration of ILC2s, including in the homeostatic and diseased kidney, are poorly understood. By integrating transcriptomic profiling, flow cytometry, live-cell imaging, and in-vivo models, we showed that renal ILCs are retained in the homeostatic kidney by the adherence of their cell-surface integrin a4ß7 to VCAM-1, E-cadherin or fibronectin on structural kidney cells. When cultured on these ligands, ILC2s demonstrated remarkable migration. Knocking down integrin-a4ß7 expression reduced ILC2 Areg production. In lupus nephritis, TLR7/9 may downregulate ILC2 expression of integrin-a4ß7, thereby both reducing Areg expression and promoting ILC2 egress. Areg loss may promote the proinflammatory-cytokine secretion by T cells. IL-33 upregulated ILC2 integrin-a4ß7 and Areg expression. Notably, IL-33 treatment enhanced survival in lupus nephritis by mitigating kidney inflammation. Thus, ILC2 adhesion may be a therapeutic target for autoimmune kidney diseases. Overall design: To investigate the role of ILCs in lupus nephritis, we used pooledkidneys from old or young MRL-lpr mice. Renal immune cells, particularly innate lymphoid cells, were further enriched using density-gradient centrifugation and an ILC enrichment kit to ensure that the scRNA-seq analysis detected a low frequency cell population of ILCs in the oldMRL-lpr kidney.