Abstract Description Background. The complement system is a key defense against pathogens and maintains intestinal homeostasis, particularly in the gut. Population studies link complement pathway mutations to IBD, but loss of C3 worsens chronic GI inflammation, suggesting complement activation produces molecules crucial for inflammation control. Our recent findings highlight the importance of complement anaphylatoxin 3a (C3a) and its receptor (C3aR) in intestinal inflammation. C3aR-deficient mice show heightened sensitivity to chronic inflammation, yet mechanisms remain unclear. The C3a-C3aR axis is known for antibacterial properties, roles in intestinal epithelial cell (IEC) proliferation, and diverse immune effects. Methods and Results. We used microbiota sequencing, imaging mass cytometry, and flow cytometry to profile bacterial and immune landscapes in C3aR-deficient and wild-type (WT) mice. C3aR reporter mice revealed C3aR expression patterns during intestinal inflammation. Loss of C3aR increased MHC-II levels on IECs, driven partly by the microbiota, as shown through fecal microbiota transplants. Bulk RNASeq revealed significant microbiota-induced transcriptional changes in IECs. During active inflammation, dendritic cells, neutrophils, and macrophages, but not IECs, upregulated C3aR expression. Conclusions. This study uncovers how C3aR loss impacts intestinal homeostasis, immune responses, and susceptibility to GI inflammation, potentially revealing novel mechanisms driving IBD progression. Funding Sources American Cancer Society RSG-24-1255025-01-IBCD NIH/NCI R01 CA258882 Topic Categories Mucosal and Regional Immunology (MUC)
Puckett et al. (Sat,) studied this question.