Alveolar macrophages (AMphi) have a fundamental role in regulating the innate immune response in host defense against infection. Recent evidence has identified Toll-like receptors (TLRs) on AMphis as having a central role in the innate immune response to invading pathogens. In response to recognition of invading pathogens. AMphis initiate a cascade of inflammatory gene expression essential for host defense, and have a fundamental role in resolving the ensuing inflammation through the removal of apoptotic inflammatory cells and release of anti-inflammatory cytokines. Following non-infectious lung injury, AMphis become activated and express many of the same inflammatory genes observed in infectious inflammation. The mechanisms that activate innate immunity and regulate the resolution of lung inflammation are unknown. Our laboratory has identified the extracellular matrix glycosaminoglycan hyaluronan (HA) as a potential regulator of innate immunity in non-infectious lung injury. Fragments of HA are generated and interact with inflammatory AMphis to induce the expression of key inflammatory mediators such as chemokines (MIP-2, MCP-1, IP-10), cytokines (TNF, IL-12), nitric oxide and the transcription factor NF-kB. The major cell surface receptor involved in HA recognition is CD44. Our preliminary data show that CD44-deficient mice fail to resolve lung inflammation and die following non-infectious lung injury with impaired clearance of apoptotic neutrophils and failure to activate TGF-beta1 In addition, we provide evidence that the TLR signaling pathway is required for cytokine induction in response to HA fragments. These data lead us to hypothesize that (1) HA fragments initiate the innate immune response to non-infectious lung injury by a TLR-dependent pathway and (2) CD44 is required to resolve innate immune responses. We will test these hypotheses in the following Specific Aims:I. Define the role of CD44 and the TLR pathway in initiating innate immune responses following non-infectious lung injury in vivo using CD44, and MyD88-deficient mice.2. Define the role of CD44 and the TLR pathway in resolving inflammation following non-infectious lung injury in vivo using CD44, MyD88-deficient mice and transgenic mice that overexpress active TGF-B about in an inducible, lung-specific manner.3. Define the mechanisms by which CD44 and the TLR signaling pathway mediate HA fragment-induced gene expression in vitro using CD44, MyD88, and TLR (1-5, 9)-deficient mice.
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