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

Abstract

BACKGROUND:

The 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.

METHODS:

We 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.

RESULTS:

BAFF-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.

CONCLUSIONS:

IL-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.

• Authors: Yuan Min Wang, Karli Shaw, Geoff Yu Zhang, Edmund Y M Chung, Min Hu, Qi Cao, Yiping Wang, Guoping Zheng, Huiling Wu, Steven J Chadban, Hugh J McCarthy, David C H Harris, Fabienne Mackay, Shane T Grey, Stephen I Alexander
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 33 Issue 5 Pg. 966-984 (05 2022) ISSN: 1533-3450 [Electronic] United States
• PMID: 35387873 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 by the American Society of Nephrology.

Chemical References

• B-Cell Activating Factor
• Homeodomain Proteins
• IL33 protein, human
• Il33 protein, mouse
• Immunoglobulin A
• Interleukin-33
• Interleukin-4

Topics

• Animals
• B-Cell Activating Factor
• Female
• Glomerulonephritis, IGA
• Homeodomain Proteins (genetics)
• Humans
• Immunity, Innate
• Immunoglobulin A
• Interleukin-33
• Interleukin-4
• Lymphocytes
• Male
• Mice
• Mice, Transgenic