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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041144-08
Application #
6849230
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Sawyer, Richard T
Project Start
1998-01-01
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
8
Fiscal Year
2005
Total Cost
$331,400
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Fanning, Laura B; Buckley, Carolyn C; Xing, Wei et al. (2013) Downregulation of key early events in the mobilization of antigen-bearing dendritic cells by leukocyte immunoglobulin-like Receptor B4 in a mouse model of allergic pulmonary inflammation. PLoS One 8:e57007
Breslow, Rebecca G; Rao, Jayanti J; Xing, Wei et al. (2010) Inhibition of Th2 adaptive immune responses and pulmonary inflammation by leukocyte Ig-like receptor B4 on dendritic cells. J Immunol 184:1003-13
Balestrieri, Barbara; Maekawa, Akiko; Xing, Wei et al. (2009) Group V secretory phospholipase A2 modulates phagosome maturation and regulates the innate immune response against Candida albicans. J Immunol 182:4891-8
Murphy, Thomas R; Legere 3rd, Henry J; Katz, Howard R (2007) Activation of protein kinase D1 in mast cells in response to innate, adaptive, and growth factor signals. J Immunol 179:7876-82
Zhou, Joseph S; Xing, Wei; Friend, Daniel S et al. (2007) Mast cell deficiency in Kit(W-sh) mice does not impair antibody-mediated arthritis. J Exp Med 204:2797-802
Zhou, Joseph S; Friend, Daniel S; Lee, David M et al. (2005) gp49B1 deficiency is associated with increases in cytokine and chemokine production and severity of proliferative synovitis induced by anti-type II collagen mAb. Eur J Immunol 35:1530-8
Feldweg, Anna M; Friend, Daniel S; Zhou, Joseph S et al. (2003) gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo. Eur J Immunol 33:2262-8
Zhou, Joseph S; Friend, Daniel S; Feldweg, Anna M et al. (2003) Prevention of lipopolysaccharide-induced microangiopathy by gp49B1: evidence for an important role for gp49B1 expression on neutrophils. J Exp Med 198:1243-51
Castells, M C; Klickstein, L B; Hassani, K et al. (2001) gp49B1-alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nat Immunol 2:436-42
Daheshia, M; Friend, D S; Grusby, M J et al. (2001) Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J Exp Med 194:227-34

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