TRPC absence induces pro-inflammatory macrophages and gut microbe disorder, sensitizing mice to colitis

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Transient receptor potential canonical (TRPC) channels regulate calcium (Ca2+) influx and are implicated in various diseases.
• TRPC channels are encoded by seven non-allelic genes and play roles in cellular signaling pathways.

Purpose of the Study:

• To investigate the role of TRPC channels in the development of colitis.
• To determine the consequences of ablating all seven TRPC genes (TRPC HeptaKO) in a mouse model of dextran sulfate sodium (DSS)-induced colitis.

Main Methods:

• Generation of TRPC HeptaKO mice lacking all seven TRPC genes.
• Induction of colitis using dextran sulfate sodium (DSS) in TRPC HeptaKO and wild-type (WT) mice.
• RNA-sequencing, flow cytometry, and gut microbiota analysis were performed on colonic tissues and fecal samples.

Main Results:

• TRPC HeptaKO mice exhibited exacerbated DSS-induced colitis compared to WT mice.
• RNA-seq revealed a highly pro-inflammatory profile in colons of DSS-treated TRPC HeptaKO mice, with increased cytokines and chemokines.
• Increased infiltration of Ly6C(hi) monocytes and neutrophils, M1 polarization of macrophages, and gut microbiota dysbiosis were observed in DSS-treated TRPC HeptaKO mice.
• Antibiotic treatment abrogated the heightened susceptibility to colitis in TRPC HeptaKO mice, suggesting a role for microbiota.

Conclusions:

• Ablation of all TRPC channels promotes DSS-induced colitis development.
• This promotion is mediated by enhanced pro-inflammatory macrophage polarization and gut microbiota disorder.
• TRPC channels are critical regulators of intestinal inflammation and gut homeostasis.