Activation of GABABR alleviates colitis by reprogramming macrophage polarization via the IRAK-M/NLRP3/NF-κB pathway.

Although the metabotropic GABA type B receptor (GABABR) has emerged as an immune modulator, its specific role in regulating the dysregulated macrophage polarization that drives inflammatory bowel disease (IBD) pathogenesis remains undefined. Utilizing a dextran sulfate sodium-induced colitis model and lipopolysaccharide-stimulated macrophages, we observed that colonic inflammation significantly downregulates GABABR expression concomitant with a pronounced shift toward M1 polarization. Pharmacological activation of GABABR with baclofen ameliorated clinical and histopathological manifestations, restored mucosal barrier integrity, and suppressed mast cell accumulation. Mechanistically, baclofen upregulated the negative regulator Interleukin-1 receptor-associated kinase M (IRAK-M), which inhibited the NOD-like receptor family pyrin domain containing 3 (NLRP3) / nuclear factor-kappa B (NF-κB) signaling cascade and promoted repolarization toward the protective M2 phenotype. The essential role of IRAK-M was confirmed via genetic knockout; such ablation abolished the protective effects of baclofen, exacerbated colitis, enhanced NLRP3/NF-κB activation, and drove M1 polarization. Transcriptomic analysis of IRAK-M-deficient mice revealed profound alterations in immune-related pathways, validating IRAK-M as a critical downstream effector. Furthermore, inhibition of NLRP3 with CY-09 and genetic deletion recapitulated the M2-promoting effects observed with GABABR activation. Collectively, these findings establish GABABR as a pivotal regulator of intestinal immune homeostasis that controls macrophage polarization through the IRAK-M/NLRP3/NF-κB axis, positioning GABABR as a promising therapeutic target for IBD.