A-Intercalated Cell Dysfunction Disrupts Renal Epithelial-Immune Balance and Impairs Host Defense During UTI

Area of Science:

• Nephrology
• Immunology
• Microbiology

Background:

• Intercalated cells (ICs) in the renal collecting duct are known for acid-base balance.
• Emerging evidence suggests ICs play a role in innate immunity.
• The specific function of A-ICs in coordinating renal immune responses during urinary tract infection (UTI) is not well understood.

Purpose of the Study:

• To investigate the role of A-intercalated cells (A-ICs) in the renal response to uropathogenic Escherichia coli (UPEC) infection.
• To examine the impact of A-IC dysfunction on bacterial load, immune cell infiltration, and inflammatory signaling in the kidney.

Main Methods:

• Utilized Ae1 R607H knock-in mice, a model of distal renal tubular acidosis (dRTA) with impaired A-IC function.
• Assessed renal response to UPEC infection, including bacterial load, gene and protein expression of antimicrobial peptides, cytokines, and chemokines.
• Analyzed immune cell infiltration and myeloid-cell composition in the kidney.

Main Results:

• Mice with A-IC dysfunction showed higher UPEC bacterial loads 24 hours post-infection.
• Increased renal expression of antimicrobial peptides (Lcn2, Lgals3, Camp) and pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) was observed.
• Dysfunctional A-ICs led to elevated chemokine levels (Cxcl2, Ccl2), excessive neutrophil infiltration, and altered myeloid-cell populations, indicating exaggerated inflammation and impaired resolution.

Conclusions:

• A-IC dysfunction is associated with increased susceptibility to UPEC infection and heightened renal inflammation.
• A-ICs are essential epithelial immunomodulators that integrate antimicrobial defense, cytokine regulation, and immune cell recruitment during UTI.
• These findings highlight A-ICs as critical players in coordinating renal innate immunity.