LUBAC activity regulates the lung epithelial response to influenza A virus infection


During influenza A virus (IAV) infection, severe lung injury and death result from an exuberant host inflammatory response, or “cytokine storm”, orchestrated by pulmonary epithelial cells. The linear ubiquitin assembly complex (LUBAC), composed of SHARPIN, HOIL-1L and HOIP, is a critical regulator of NF-κB-dependent inflammation. To determine the impact of LUBAC-dependent signaling in the host response to IAV infection, we used mice with lung epithelial specific deletions of HOIL-1L (SPCcre/HOIL-1Lfl/fl) or HOIP (SPCcre/HOIPfl/fl) and assessed survival, inflammation (cytokines, myeloid and lymphoid cell subsets) and lung injury (barrier permeability, total cellular infiltration) in a model of IAV infection. SPCcre/HOIL-1Lfl/fl mice, which have reduced LUBAC activity, were markedly protected during IAV infection with increased survival, and reduced inflammation and lung injury compared to WT counterparts. In contrast, SPCcre/HOIPfl/fl mice, which lack the catalytic unit of LUBAC, had worsened lung injury and decreased survival. Additionally, GWAS data revealed a SNP predicted to result in an amino acid change in the “catalytic core” of HOIP was associated with a worse acute respiratory distress syndrome prognosis. These results are in agreement with our finding that during IAV infection, HOIL-1L is upregulated in both human and mouse alveolar epithelial cells in an autocrine and/or paracrine manner that is dependent on activation of the type I interferon receptor. This upregulation, mediated by the transcription factor interferon regulatory factor 1, is maladaptive and contributes to hyper-inflammation. Taken together these results suggest that while a reduction in the inflammatory response is beneficial, ablation of the LUBAC-dependent lung epithelial-driven response worsens lung injury and increases mortality. Thus, we propose that lung epithelial LUBAC acts as a molecular rheostat that could be selectively targeted to modulate the immune response in patients to reduce severe IAV-induced “cytokine storm”.

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