@article {Ngo2022.01.05.475168, author = {Minh Dao Ngo and Stacey Bartlett and Helle Bielefeldt-Ohmann and Cheng Xiang Foo and Roma Sinha and Buddhika Jayakody Arachige and Sarah Reed and Thomas Mandrup-Poulsen and Mette Marie Rosenkilde and Katharina Ronacher}, title = {A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection}, elocation-id = {2022.01.05.475168}, year = {2022}, doi = {10.1101/2022.01.05.475168}, publisher = {Cold Spring Harbor Laboratory}, abstract = {We previously reported that the oxidised cholesterol-sensing receptor GPR183 is significantly downregulated in blood from tuberculosis (TB) patients with diabetes compared to TB patients without co-morbidities and that lower GPR183 expression in blood is associated with more severe pulmonary TB on chest-x-ray consistent with observations in dysglycemic mice. To further elucidate the role of this receptor and its endogenous high affinity agonist 7α,25-di-hydroxycholesterol (7α,25-OHC) in the lung, we studied high fat diet (HFD)-induced dysglycemic mice infected with M.tuberculosis.We found that the 7α,25-OHC-producing enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) were highly upregulated upon M. tuberculosis infection in the lungs of normoglycemic mice, and this was associated with increased expression of GPR183 indicative of effective recruitment of GPR183-expressing immune cells to the site of infection. We demonstrated that CYP7B1 was predominantly expressed by macrophages in the centre of TB granulomas. Expression of CYP7B1 was significantly blunted in lungs from HFD-fed dysglycemic animals and this coincided with delayed recruitment of macrophages to the lung during early infection and more severe lung pathology. GPR183 deficient mice similarly had reduced macrophage recruitment during early infection demonstrating a requirement of the GPR183/oxysterol axis for macrophage infiltration into the lung in TB.Together our data demonstrate that oxidised cholesterols and GPR183 play an important role in positioning macrophages to the site of M. tuberculosis infection and that this is impaired by HFD-induced dysglycemia, adding a mechanistic explanation to the poorer TB outcomes in patients with diabetes.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2022/01/06/2022.01.05.475168}, eprint = {https://www.biorxiv.org/content/early/2022/01/06/2022.01.05.475168.full.pdf}, journal = {bioRxiv} }