Immune Cell Characteristics in a Gut-Kidney Axis-Induced Mouse Model of IgA Nephropathy: The Upregulated Dendritic Cells and Neutrophils.

BACKGROUND: IgA nephropathy (IgAN) is the leading type of primary glomerulonephritis, significantly contributing to chronic kidney disease (CKD) and renal failure. The pathogenesis of IgAN is the multi-hit hypothesis regarding overproduction and accumulation of galactose-deficient (Gd-IgA1). Recent findings have revealed gut microbiota dysbiosis and immune responses are essential in the development of IgAN, attracting increasing attention. This study aimed to map mucosal immune cells in IgAN influenced by gut microbiota, investigating the role of innate immune cells in kidney damage. METHODS: Fecal samples were acquired from both patients and controls for subsequent animal experiments. Mice received a broad-spectrum antibiotic cocktail to eliminate their intestinal microflora, followed by a gavage with fecal microbiota from clinical individuals. Murine intestinal and kidney tissues were collected for flow cytometry. Intestine and kidney histopathology, immunofluorescence, and inflammatory cytokine expression were assessed in the murine models. The mucosal epithelium's structure and function, along with the innate immune cell response, were analyzed. RESULTS: Mice exhibited the IgAN phenotype following colonization with gut microbiota from IgAN patients. These mice (IgAN-FMT mice) showed renal dysfunction and increased pathology of tissue injury in both intestine and kidneys. IgAN-FMT mice showed heightened pro-inflammatory cytokine (IL-6 and TNF-α) activity, greater antibody (IgA and complement C3) deposition and decreased expression of mucosal barrier protein (ZO-1, Occludin) compared to the control group. Furthermore, CD11c(+)dendritic cells were more abundant in the murine intestine and kidneys compared to the control group. CONCLUSION: The gut-kidney axis, including microbiota homeostasis and innate immune cell response, contributes to the pathogenesis of IgAN. Gut dysbiosis and hyperactivated immune cells like CD11c(+)dendritic cells can affect the mucosal barrier and exacerbate the renal damage, being novel insights into immunotherapeutic strategies for IgAN.