Gpr84 activation induces anti-mycobacterial defense in macrophages via MAPK signaling.

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), remains a significant global health threat. The complete pathogenesis of Mtb infection within the host remains insufficiently elucidated, highlighting the urgent need for research focused on host-directed therapeutic strategies targeting infected immune cells. G protein-coupled receptor 84 (Gpr84), an inflammatory receptor expressed on the surface of immune cells, is known to induce inflammatory responses upon activation. We hypothesized that Gpr84 plays a pivotal role in regulating the macrophage response to Mtb infection. In this study, we investigated the role of Gpr84 in controlling intracellular Mtb survival within macrophages. Genetic knockdown of Gpr84 using small interfering RNA (siRNA) significantly increased the Mtb burden. Conversely, treating Mtb-infected macrophages with the Gpr84 agonist 6-n-octylaminouracil (6-OAU) led to a pronounced, dose-dependent reduction in bacterial load. Mechanistically, Gpr84 activation enhanced the production of pro-inflammatory cytokines and robustly increased the activation of the MAPK pathway (Erk and Jnk), suggesting a direct mechanism for bacterial clearance. Our findings define Gpr84 as a critical component of host anti-mycobacterial defense, inhibiting Mtb growth in macrophages via the MAPK signaling cascade. This study strongly identifies Gpr84 as a promising host-directed therapeutic target for combating drug-resistant TB.