As potent first defenders against infection, neutrophils, or polymorphonuclear leukocytes (PMN), eliminate pathogens with a powerful repertoire of antimicrobial weapons. Although essential for protection, uncontrolled PMN activity damages host tissues and is associated with a number of inflammatory diseases including rheumatoid arthritis (RA). It has been shown that the adaptor molecule SLP-76 is a critical mediator of in vitro PMN activation following stimulation through Fc gamma receptors (FcyR) and integrins. Interestingly, mice with targeted loss of SLP-76 within the PMN compartment maintain the ability to kill the bacterial strain S. Aureus in vivo, but have reduced vascular and tissue damage in a model of localized inflammation. This proposal is designed to further understand the mechanisms by which SLP-76 and the structurally related molecule SLP-65 (BLNK), coordinate PMN activation. Through the use of targeted genetic mutations in mice, these studies will examine how SLP-76 and BLNK coordinate signaling events regulating in vitro and in vivo PMN activation, and determine whether SLP-76 and/or BLNK-dependent PMN functions contribute to inflammatory disease. Information gained from these studies may elucidate novel signaling targets that can be therapeutically manipulated in order to minimize the pathological consequences of PMN activation, as seen in patients with inflammatory arthritis, without compromising PMN bactericidal capabilities.
Aim 1 : Analyze the ability of membrane-targeted SLP-76 to support FcyR and integrin signaling in PMN.
Aim 2 : Evaluate PMN activation in the absence of the SLP-76 homologue BLNK.
Aim 3 : Characterize the propagation of serum-induced arthritis in the absence of SLP-76 and/or BLNK. Relevance to Public Health: Neutrophils are an essential cell of our immune system that eliminate infections, but can contribute to inflammation and tissue damage when their activity is misregulated, such as in rheumatoid arthritis. The proposed experiments use genetic mutations in mice to study neutrophil regulation in a live animal, which includes a disease model of rheumatoid arthritis. These studies will help identify new ways to minimize the destructive forces of neutrophil activation, without compromising their ability to fight infections.
