Title : Novel regulatory mechanisms of innate immunity and inflammation
Abstract:
Myeloid cells are the major players of innate immunity and inflammation. The functionality of myeloid cells is controlled by innate immune receptor signaling, which is critically regulated by a cytoplasmic adaptor protein termed TRAF3. Ablation of TRAF3 from myeloid cells does not affect the maturation or homeostasis of macrophages and neutropvhils in young adult mice. However, aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation, tumors, and bacterial infection that affect multiple organs. Using a chronic inflammation model induced by repeated injections of heat-killed Bacillus Calmette-Guérin (BCG), we demonstrated that TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell (MDSC) expansion during chronic inflammation. Interestingly, our studies of mixed bone marrow chimeras revealed that TRAF3 restrains MDSC expansion via both cell-intrinsic and cell-extrinsic mechanisms. We next sought to identify the internal trigger of chronic inflammation and bacterial infection in these mice. We detected gut dysbiosis and transmigration of commensal bacteria to the liver in aging M-Traf3-/- mice using 16s rRNA gene sequencing of fecal bacterial DNA and bacterial culture of liver homogenates, respectively. To determine if gut dysbiosis and bacterial transmigration cause chronic inflammation and bacterial infection, we treated mice with broad-spectrum antibiotics. We found that depletion of commensal bacteria with antibiotics effectively prevented spontaneous chronic inflammation and bacterial infection in aging M-Traf3-/- mice. Taken together, our findings indicate that TRAF3 proteins expressed in myeloid cells critically regulate innate immunity and play indispensable roles in maintaining the symbiosis of gut microbiota and inhibiting chronic inflammation and commensal bacterial infection.
