GPR183 oxysterol axis is dysregulated at the site of disease during M. tuberculosis infection
Stacey Bartlett1, Minh Dao Ngo1, Roma Sinha1, Cheng Xiang Foo1, and Katharina Ronacher1,2*
1 Mater Research Institute - The University of Queensland, Brisbane, QLD, Australia; 2 Australian Infectious Diseases Research Centre – The University of Queensland, Brisbane, QLD, Australia.
Oxidized cholesterols have emerged as important signalling molecules of immune function, but little is known about the role of these oxysterols during mycobacterial infections. We previously found that 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 and was associated with TB disease severity on chest x-ray. Activation of GPR183 by its endogenous high affinity agonist 7α,25-dihydroxycholesterol (7α,25-OHC) reduced growth of Mtb in primary human monocytes, and this effect was reversed in the presence of the antagonist for GPR183, GSK682753A. Growth inhibition was associated with reduced IFN-β expression and enhanced autophagy. GPR183 knockout (KO) mice showed significantly increased mycobacterial burden in the lungs and dysregulated IFN responses during early infection.
To determine whether the dysregulation of the GPR183/oxysterol axis is linked to diabetes or solely to TB disease severity we established a murine model of high fat diet-induced hyperglycaemia. Similar to our observations in diabetes patients, hyperglycaemic mice had reduced expression of Gpr183 in blood after Mtb infection compared to normoglycaemic control mice. While Gpr183 expression increased in the lungs of both hyperglycaemic and normoglycaemic mice upon Mtb infection, hyperglycemic mice had significantly reduced expression of Cyp7b1, the enzyme converting 25-hydroxycholesterol to 7α,25-OHC. This was associated with a trend towards increased bacterial lung burden. A diet-reversal experiment significantly increased lung Cyp7b1 expression and significantly reduced lung Mtb burden.
Overall, we have demonstrated that GPR183 plays a role in efficient mycobacterial control during the innate immune response during Mtb infection. We further show here that the GPR183/oxysterol axis is modified by high-fat diet in a murine model and is potentially key regulator of bacterial lung burden in diabetes patients.