Adipose Tissue Inflammation in Influenza Infection Severity

摘要

ABSTRACT The obesity pandemic continues unabated, afflicting >500 million people worldwide. Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to Influenza infection. Altered immune cell function (e.g. cytokine production) is often perceived as a key causative factor for increased lung tissue damage. However, the contribution of adipocytes, the dominantly altered cell type in obesity with immune-like properties, to Influenza pathogenesis remains largely ignored. Notably, obesity promotes adipocyte skewing towards a proinflammatory state and amplifies their immune-like contribution. Here we propose to examine the contribution of adipocyte inflammatory capacity to influenza disease pathogenesis. Our novel preliminary data strongly suggest that influenza-induced type I interferon (IFN) sensing skews adipocyte-specific inflammatory capacity, and promotes systemic and tissue inflammation that correlates with disproportionate lung tissue damage in mice. Our preliminary findings indicate that: Obese mice infected with influenza, compared to lean controls, exhibit: (a) increased mortality; (b) more severe lung tissue pathology; (c) increased lung edema; and (d) elevated lung IL-6 levels. Further, we show that influenza infection: (e) directly shapes white adipose tissue (WAT) immune cell infiltration and increases WAT type I IFN/IFNAR axis activation; and (f) induces adipocyte IL-6 inflammatory responses. Lastly, we show that: (g) obesity amplifies adipocyte inflammatory vigor via the type I IFN/IFNAR axis; (h) adipocytes contribute to systemic inflammatory cytokine production; and (i) adipocyte-secreted factors exacerbate lung epithelial cell inflammation. Our data and existing literature support a novel hypothesis that IFNAR-dependent activation of adipocyte inflammatory capacity promotes adipocyte IL-6 production and amplifies influenza infection-driven lung disease severity in obesity. We propose to test this hypothesis by: (i) determining the impact of Influenza infection on adipocyte inflammatory capacity and lung tissue damage in obesity (Aim 1); (ii) determining the contribution of adipocyte-centric IL-6 production on Influenza-associated tissue damage in obesity (Aim 2). Our studies will enhance the knowledge of adipocyte-driven inflammatory vigor and the impact of such inflammation on human disease. Considering the global trend towards a more obese population, defining the contribution of these cellular inflammatory processes will provide a robust platform for discovery of novel therapeutic targets to reduce the clinical burden of influenza.