We further demonstrate that GPR183 activation by 7α,25-OHC reduces IFN-β expression and secretion in Mtb-infected primary MNs and targeted GPR183 knockdown significantly upregulating IRFs and IFNB1. Similarly, gene expression of IRF1, IRF5, and IRF7 is up-regulated in TB + T2D patients compared to TB patients and corresponds with down-regulation of GPR183, thereby demonstrating that GPR183 expression is associated with IFN regulatory factors during human TB, and GPR183 is a negative regulator of type I IFNs in Mtb-infected human MNs. Here, IRF5 is linked to type 2 diabetes mellitus.