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

Although the metabotropic GABA type B receptor (GABA_BR) 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 GABA_BR expression concomitant with a pronounced shift toward M1 polarization. Pharmacological activation of GABA_BR 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 GABA_BR activation. Collectively, these findings establish GABA_BR as a pivotal regulator of intestinal immune homeostasis that controls macrophage polarization through the IRAK-M/NLRP3/NF-κB axis, positioning GABA_BR as a promising therapeutic target for IBD.