A Blunted GPR183/Oxysterol Axis During Dysglycemia Results in Delayed Recruitment of Macrophages to the Lung During Mycobacterium tuberculosis Infection

Background We previously reported that reduced GPR183 expression in blood from tuberculosis (TB) patients with diabetes is associated with more severe TB. Methods To further elucidate the role of GPR183 and its oxysterol ligands in the lung, we studied dysglycemic mice infected with Mycobacterium tuberculosis (Mtb). Results We found upregulation of the oxysterol-producing enzymes CH25H and CYP7B1 and increased concentrations of 25-hydroxycholesterol upon Mtb infection in the lungs of mice. This was associated with increased expression of GPR183 indicative of oxysterol-mediated recruitment of GPR183-expressing immune cells to the lung. CYP7B1 was predominantly expressed by macrophages in TB granulomas. CYP7B1 expression was significantly blunted in lungs from dysglycemic animals, which coincided with delayed macrophage infiltration. GPR183-deficient mice similarly had reduced macrophage recruitment during early infection. Conclusions Taken together, we demonstrate a requirement of the GPR183/oxysterol axis for positioning of macrophages to the site of infection and add an explanation to more severe TB in diabetes patients. Mycobacterium tuberculosisinfection increases production of oxidized cholesterols in the lung, which facilitates the recruitment of immune cells expressing the oxysterol-sensing receptor GPR183 to the site of infection. The GPR183/oxysterol axis is blunted during dysglycemia resulting in delayed macrophage recruitment.

Automated summary

In tuberculosis patients, reduced expression of GPR183 in diabetes patients is associated with more severe tuberculosis. Mycobacterium tuberculosis infection leads to the production of oxidized cholesterols in the lung, facilitating the recruitment of immune cells expressing the oxysterol-sensing receptor GPR183 to the site of infection. The GPR183/oxysterol axis is blunted during dysglycemia, resulting in delayed macrophage recruitment.