Metabolism and immune function are tightly linked. Oxidized cholesterols have recently emerged as important signaling molecules of immune function, but little is known about the role these oxysterols play during M. tuberculosis (Mtb) infection.
We found that mRNA expression of the oxysterol receptor GPR183 was reduced in blood from patients with tuberculosis (TB) and type 2 diabetes (T2D) compared to TB patients without T2D. Consistent with our observations in patients, hyperglycaemic Mtb infected mice had reduced peripheral GPR183 expression, reduced expression of the oxysterol producing enzyme CYPB1 and increased lung pathology. We therefore hypothesized that the oxysterol/GPR183 axis plays a role in mycobacterial control and herein demonstrate that GPR183 activation by 7-alpha-25-hydroxycholesterol (7a-25OHC) reduced growth of Mtb and M. bovis BCG in primary human monocytes, with this effect being abrogated by the GPR183 antagonist GSK682753. Growth inhibition was associated with reduced IFN-b and IL-10 expression and increased autophagy. Knockdown of GPR183, which possess basal constitutive activity, led to increased expression of IFN regulatory factors (IRF-3, IRF-5, IRF-7) and IFN-b.
Together, our data demonstrate that GPR183 is a novel regulator of intracellular mycobacterial control and of type I IFNs in Mtb-infected human monocytes. Therefore, the oxysterol/GPR183-axis may contribute to disease severity and poor treatment outcomes in TB-T2D patients, and GPR183 may be a promising target for host-directed therapy.