Infectious diseases such as influenza and coronavirus disease 2019 (COVID-19) cause a significant burden to global health. Severe forms of these respiratory infections are often characterized by hyper-inflammation due to excessive immune cell infiltration to the site of infection and pro-inflammatory cytokine production, also referred to as cytokine storm. However, the immunological mechanisms underlying the development of a cytokine storm remain elusive. We have identified a novel player and important regulator of immune cell recruitment to the lung, the oxidized cholesterol receptor GPR183, which is expressed on cells of the innate and adaptive immune system. 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.
Influenza A virus 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. We have further demonstrated in a mouse model of SARS-CoV-2 infection that GPR183 KO mice had less severe weight loss compared to WT mice. Infected WT mice treated with GPR183 antagonist had less severe SARS-CoV-2 infection characterised by less drastic weight loss and symptoms and faster recovery compared to infected WT mice given vehicle. Therefore, we provide preclinical translational evidence that modulation of GPR183 activity shows promise for improving viral respiratory infections outcomes.