Chronic alcohol consumption causes alveolar macrophage derangements via alterations in hyaluronic acid 2794

Abstract Description Alcohol use disorder (AUD) increases risk for pneumonia by 2-4-fold via impaired phagocytosis in ∼56% of lung macrophages, suggesting heterogeneity in lung macrophages’ immune response to bacterial infections. Understanding the mechanistic underpinnings of how chronic ethanol (EtOH) consumption alters the immunometabolic phenotypes of monocyte-derived alveolar macrophages (MoAMs) and tissue-resident alveolar macrophages (RAMs) is imperative to developing therapies to target dysregulated lung macrophages. Hyaluronic acid (HA) is an extracellular matrix polysaccharide whose signaling directs inflammation in numerous lung diseases. Low molecular weight HA signaling is pro-inflammatory, while high molecular weight HA signaling is anti-inflammatory. Thus, we hypothesized that AUD/EtOH dysregulates immunometabolism in AMs via altered HA. MH-S cells, a murine RAM cell line, were treated ± chronic EtOH (0.08%, 72h). In addition, MoAMs and RAMs were isolated from non-AUD control and AUD individuals (median AUDIT score=21). In MH-S cells, EtOH increased HA via upregulation of HA synthase 2 and decreased hyaluronidase 1. EtOH also suppressed mitochondrial bioenergetics, which were reversed with a HA synthase inhibitor. Further, AUD increased the number of MoAMs compared to RAMs, but AUD MoAMs were pro-inflammatory with normal phagocytic function and AUD RAMs were anti-inflammatory with impaired phagocytosis. Our data support therapeutic targeting of HA to improve lung immunity in AUD. Funding Sources Supported by NIAAA/NIH R01AA026086. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)