Temporal regulation of pulmonary inflammation by MyD88 alternative pre-mRNA splicing

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ABSTRACT Acute inflammatory diseases of the lungs affect more than 100 million people in the U.S. annually. The acute inflammatory response in these patients is required to combat infection but also causes significant tissue damage. Thus, proper resolution of inflammation is critical for patient recovery. Lung airspace macrophages (AMs) serve as key orchestrators of the inflammatory response, functioning in both the initiation and resolution of inflammation. However, the mechanisms used by AMs to direct the resolution of inflammation are incompletely understood. Moreover, two different AM subsets modulate inflammation. Resident AMs are present in the airspaces throughout life; they serve as first responders to pathogens but their inflammatory programs are quickly down-regulated. Recruited AMs arise from circulating monocytes that migrate to the lung during inflammation; inflammatory mediator production by these cells is more persistent than that of resident AMs. The mechanisms that drive the divergent effects of these AM populations on inflammation remain to be elucidates. We have found that alternative pre-mRNA splicing of MyD88, a signaling adaptor that functions in multiple Toll-like receptor and IL-1 receptor signaling pathways, plays a key role in terminating pro- inflammatory mediator production in AMs. Thus we hypothesize that altered splicing of MyD88 provides a central brake on AM pro-inflammatory responses and serves to limit persistent inflammation. We further postulate that the role of MyD88 alternative splicing differs in different AM subpopulations. To test this hypothesis, we will investigate the physiological effect of alternative MyD88 splicing in: (1) mouse resident AMs ex vivo and in vivo, (2) mouse recruited AMs ex vivo and in vivo, and (3) human AMs isolated from patients with acute inflammatory lung disease. These studies will demonstrate the potential utility of targeting this regulatory mechanism to treat patients with acute inflammatory lung disease.