TREM-1 in Lung Immune Response

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DESCRIPTION (provided by applicant): Abstract: Lung infections and sepsis caused by P.aeruginosa are a leading cause of death in the intensive care unit. The failure rate for antibiotic treatment for P. aeruginosa pneumonia is high and antibiotic resistance that develops during therapy is associated with persistent pneumonia and development of multi-organ dysfunction syndrome. Therefore there is an urgent need to develop immunomodulatory strategies for P.aeruginosa lung infections. It is becoming evident that immunoglobulin receptors and intracellular proteins such as nucleotide oligomerization domains co-operate with TLRs and are critical in defining the innate host response to bacteria. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on macrophage and neutrophils. Blockade of TREM-1 improves survival in lethal animal models of sepsis. These receptors are thus emerging as potent amplifiers of TLR initiated inflammatory responses however there is limited data on the mechanisms by which TREM-1 expression is regulated in response to bacteria and there is little to no information about how these receptors modulate host response to invading pathogens. We were the first to show that TREM-1 activation in response to LPS is transcriptionally controlled (1). While NF-¿B activates the TREM-1 gene, PU.1 inhibits the expression of TREM-1 in response to LPS. Second, we have shown that MyD88 dependent and independent signaling determines the expression of TREM-1 in response to specific TLR ligands (2). We have also defined the functional consequences of silencing TREM-1 gene in macrophages which include altered availability of key signaling molecules downstream of TLR4 activation (3). Our new data shows that TREM-1 is induced in vivo in mice in response to P.aeruginosa and in human lungs with septic lung injury. TREM-1 activation in macrophages provides a positive feedback to the TLR induced inflammation by upregulating key biomolecules such as IL-6 and IL-23 thus exaggerating inflammation and impeding the immune capacity of macrophages to kill bacteria in vitro. Together these data indicate a significant crosstalk between TLR and TREM-1 signaling and suggest a key role for TREM-1 in defining the host immune response. Most importantly by using novel nanomicellar preparation we have shown that blockade of TREM-1 attenuates lung inflammation in mice in vivo. As a whole our published and preliminary studies suggest two fundamentally new mechanisms to be pursued in this application: (1) TREM-1 expression by transcriptional control and epigenetic modification in response to bacteria (2) mechanisms by which TREM-1 signaling exaggerates inflammation and inhibits host protective response to invading bacteria using genetic and novel nanomedicine approach. Our findings have led to the hypothesis that activation of TREM-1 in response to P.aeruginosa is regulated by NF-¿B and PU.1. TREM-1 activation in macrophages plays a pivotal role in defining the host response to bacteria. Thus blockade of TREM-1 will enhance host immune capacity to P.aeruginosa lung infections. We propose three interrelated specific aims:1) Define the molecular mechanisms by which TREM-1 expression is regulated by p65 and PU.1 in vitro in macrophages in response to P.aeruginosa. 2) Elucidate the role of TREM-1 signaling in macrophages and in vivo in host immune response to P. aeruginosa infection. 3) Develop novel TREM-1 blocking nanomicelles for immunomodulatory therapies for P.aeruginosa pneumonia. Nosocomial pneumonia caused by P.aeruginosa is a leading cause of morbidity and mortality in critically ill patients and the Department of Veterans Affairs is the largest worldwide single provider of critical care services. Completion of these studies will provide an in depth understanding of the contribution of TREM-1 in lung immune response and will lay the ground work for developing immunomodulatory therapies that will have a significant impact on treatment of life threatening infections such as P.aeruginosa.