Inflammation in response to microbial infections is an essential component for survival, yet excessive or prolonged inflammatory responses can be detrimental. A major gap in our knowledge is how receptors that initiate innate inflammatory responses to microbial agents are counterregulated to prevent tissue damage. The gp49B1 receptor is expressed on the surface of mast cells, macrophages, neutrophils, and NK cells and counterregulates activating receptors of the adaptive immune system in vitro and in vivo. However, we have found by generating gp49B1 null mice that this receptor also inhibits inflammation induced by two mediators of innate responses, namely, lipopolysaccharide (LPS) and stem cell factor (SCF), derived from bacteria and stromal cells, respectively. The broad, long-term objective of this application is to understand how gp49B1 counterregulates inflammation induced by innate responses in vivo. We will achieve this objective by testing a central hypothesis that expression of gp49B1 decreases the sensitivity of mast cells, neutrophils, and/or macrophages to innate activating stimuli, which reduces the production of and responses to proinflammatory mediators so as to limit pathologic consequences of inflammation in vivo. We will test the central hypothesis of this application by pursing the following Specific Aims. First, we will establish the role of gp49B1 in regulating innate inflammatory responses to LPS and protective responses to bacterial infection in vivo. Second, we will determine the extent to which gp49B1 selectively inhibits the mast cell-activating effects of SCF while preserving its growth-promoting effects. Successful completion of the proposed studies will provide knowledge that will ultimately lead to a better understanding of how natural or intervention-based alterations in gp49B1, which is a mouse homologue of the human leukocyte immunoglobulin-like receptor (LIR) 5, affect the course of inflammatory responses to microbial infections.
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