LSC - 2024 - Deciphering the paradoxical immunoregulatory roles of ADAM metallopeptidase with thrombospondin type 1 motif-4 (ADAMTS4) in lung inflammation

<bold>Background:</bold> Chronic and severe lung inflammations are characterized by different immune dysregulations and structural alterations. We reported a critical role for ADAMTS4 in immunopathology of influenza virus-induced lung inflammation (Boyd et al. Nature 2020;587 (7834):466-471). However, the role of ADAMTS4 in various states of lung inflammation has never been explored. <bold>Aims and objectives::</bold> We sought to examine the role of ADAMTS4 in chronic and severe lung inflammation. <bold>Methods::</bold> For the chronic model, wildtype and ADAMTS4-/- mice were challenged with house dust mites over 5 weeks. For the severe model, mice were co-infected with Streptococcus pneumonia and influenza virus for 9 days. We characterized the lung infiltrating immune cells and mapped the activation state of structural cells. We evaluated lung function, transcriptional profile, and lung dysregulation factors. <bold>Results::</bold> In the chronic model, ADAMTS4-/- mice had significantly reduced lung eosinophils, mucus secretion, and airway resistance, while in severe model we found that ADAMTS4 expression was critical for survival, reduced neutrophils, and bacterial clearance. The reduction of IL4, IL5, IL13, and IgE in ADAMTS4-/- mice in chronic model was contrasted by a marked upregulation in IL6, TNFa, MPO, NOD1, and versican expression in the severe model. <bold>Conclusion::</bold> Our findings demonstrate unprecedented roles for ADAMTS4 in lung immunopathology under various inflammatory states. While targeting ADAMTS4 could harbor a therapeutic potential in chronic lung inflammation, its inhibition may be a predisposing factor for bacterial pneumonia by enhancing bacterial adhesion and transmigration.