Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor

Abstract

BackgroundThe cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy.MethodsWe administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice.ResultsBAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33–treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33–stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)–depleted splenocytes. Wild-type mice infused with IL-33–treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution.ConclusionsIL-33–expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.

Causality between allergic diseases and kidney diseases: a two-sample Mendelian randomization study

“…Inflammation: Inflammatory markers in the bloodstream, such as c-reactive protein (CRP) ( 36 ) and white blood cell count ( 37 ), are common immunological indicators. These markers typically rise during disease activity or exacerbation ( 38 , 39 ).…”

Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease

“…In the context of the kidney, IL-33 has been implicated in the development and progression of several diseases etiologies, including acute kidney injury, CKD, glomerulonephritis, and renal allograft fibrosis. 38 , 40 , 50 , 74 , 75 , 76 , 77 , 78 In several mouse models of renal disease, blocking IL-33 has also been shown to reduce disease severity. 74 , 75 , 79 , 80 , 81 Our investigation of IL-33 in DKD has provided additional insight into the important immunomodulatory effect of this alarmin.…”