Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

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SUMMARY Chronic heavy drinking (CHD) is associated with multiple adverse health outcomes including increased incidence of liver disease, cardiovascular disease, cancer, and/or infectious disease. Given the increased incidence of viral, bacterial, and/or fungal infections often seen in patients with CHD, this suggests that alcohol can have a significant impact on the host immune response and host defense. Several studies have shown that the most dramatic and consistent changes induced by CHD are evident in the innate immune arm. Using a non-human primate (NHP) model of voluntary ethanol self-administration, we have reported significant defects in monocytes/macrophages. CHD is also associated with increased risk for respiratory infection and disease, notably acute respiratory distress disease syndrome (ARDS). Alveolar macrophages play a critical role in the inflammatory process associated with ARDS. More recently, we have reported that alveolar macrophages from CHD macaques exhibit signs of increased oxidative damage, generate an exaggerated inflammatory response, and dampened anti-bacterial and anti-viral immune responses; thereby providing a link between CHD and increased incidence of ARDS. However, exact mechanisms remain poorly understood. The purpose of this diversity supplement is to support Dr. Jamie Sturgill to test the hypothesis that dysregulation of ceramide levels and signaling in alveolar macrophage with CHD leads to exacerbated inflammatory responses. Previous work by the Sturgill lab has shown that ceramide is a critical sphingolipid in the lung and that alterations of ceramide signaling lead to increased reactive oxygen production, macrophage inflammatory responses, apoptosis, and pulmonary dysfunction. Moreover, ceramide levels are increased in patients with alcoholic liver disease. Thus, ceramide is a logical target to investigate. This supplement is in line with the parent R01 that is investigating mechanisms of aberrant inflammation by circulating monocytes. This supplement will allow Dr. Sturgill to address a critical gap in our knowledge in a focused and mentored project while honing technical skills and gaining expertise in the field of alcohol and immunity in order to facilitate her ability to submit an R01 proposal to further interrogate the effects of CHD on pulmonary disease.