Metabolic diseases including diabetes are a major risk factor for both bacterial and viral respiratory infections. The immune-metabolic mechanisms underlying this association remain poorly understood. Oxidized cholesterols, so called oxysterols, have emerged as important signalling molecules of immune function. The oxysterol 7a,25-hydroxycholesterol (7a,25OHC) is the endogenous high affinity ligand for the oxysterol-sensing receptor GPR183, which is expressed on cells of the innate and adaptive immune system. GPR183 expressing immune cells migrate towards a gradient of the 7a,25OHC to position them to secondary lymphoid organs. However, little is known about oxysterols and GPR183 in the lung. Our team recently demonstrated that oxidised cholesterols and the GPR183 play an important role in pulmonary tuberculosis (TB) pathogenesis (1). In addition, we demonstrated that activation of GPR183 induces autophagy resulting in reduced mycobacterial burden in macrophages and that GPR183 is a negative regulator of type I IFNs. While type I IFNs contribute to lung pathology in TB they are essential for anti-viral responses. This hence raises additional questions: What is the role of GPR183 in viral respiratory infections in hosts with and without metabolic dysfunction and can modulating the activity of GPR183 benefit viral respiratory infection outcomes?
Using Influenza A virus (IAV) as our model pathogen, we show here that GPR183 plays a role in the immune response to IAV in the lung. Infected GPR183KO mice had lower pro-inflammatory profile upon severe IAV infection compared to WT C57BL/6 mice. WT mice treated with GPR183 antagonist NIBR189 demonstrated lower pro-inflammatory cytokine production and reduced infiltration of macrophages, with neutrophil and T cell subsets not being affected. Therefore, we provide preclinical translational evidence that modulation of GPR183 activity shows promise for improving lung inflammation during viral respiratory infections.