Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient miceResearch in context
Yusuke Kinashi,
Keisuke Tanaka,
Shunsuke Kimura,
Masato Hirota,
Seiga Komiyama,
Tomoko Shindo,
Akinori Hashiguchi,
Daisuke Takahashi,
Shinsuke Shibata,
Shin-Ichiro Karaki,
Hiroshi Ohno,
Koji Hase
Affiliations
Yusuke Kinashi
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
Keisuke Tanaka
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
Shunsuke Kimura
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan; Corresponding author.
Masato Hirota
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
Seiga Komiyama
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
Tomoko Shindo
Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan
Akinori Hashiguchi
Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan; Depatment of Pathology, Keio University School of Medicine, Tokyo, Japan
Daisuke Takahashi
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
Shinsuke Shibata
Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan; Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
Shin-Ichiro Karaki
Laboratory of Physiology, Department of Environmental and Life Sciences, University of Shizuoka, Shizuoka, Japan
Hiroshi Ohno
RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Immunobiology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan; Laboratory for Immune Regulation, Graduate School of Medicine, Chiba University, Chiba, Japan
Koji Hase
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan; Institute of Fermentation Sciences (IFeS), Faculty of Food and Agricultural Sciences, Fukushima University, Fukushima, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan; Corresponding author. Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.
Summary: Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.
