Regulation of cellular functions by the plasminogen receptor, Plg-RKT

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Project Summary/Abstract The plasminogen activation system extensively regulates the inflammatory response in a broad range of tissues. Inflammation is essential for maintenance of normal tissue homeostasis and its dysregulation has a broad pathologic impact, including development of fibrosis, scarring, aberrant wound healing, infection, sepsis, autoimmune disease and asthma. A critical gap in knowledge is understanding the mechanisms by which plasminogen communicates with cells to regulate inflammatory responses. Plg-RKT is a novel integral membrane protein that binds plasminogen via a C-terminal lysine exposed on the cell surface and promotes cell surface plasminogen activation. The long-term goal of our laboratory is to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes. This proposal is based on new data showing that Plg-RKT promotes expression of CCL2, a key mediator of the pro-inflammatory response, and a potential intervention point for the treatment of diseases with an inflammatory component. Additional results support the provocative concept that regulation of CCL2 expression, rather than cell surface proteolysis of extracellular matrix, appears to be the primary mechanism for plasminogen/Plg-RKT control of mononuclear cell recruitment in the inflammatory response in vivo. The central hypothesis to be addressed is that plasmin(ogen)/Plg-RKT- dependent promotion of CCL2 expression is the primary mechanism for promotion of plasmin(ogen)/Plg-RKT- dependent mononuclear cell recruitment in the inflammatory response. The hypothesis will be tested in murine models of pleurisy and peritonitis. And we will investigate the role of Plg-RKT in the inflammatory response in asthma because in T helper type 2 (Th2) immune-related diseases, such as asthma, CCL2 is expressed at high levels and its neutralization in animal models ameliorates disease. The objectives of this proposal are to investigate the role of Plg-RKT in CCL2 synthesis in vivo and assess its impact on Plg-RKT-dependent mononuclear cell recruitment and to examine the role of Plg-RKT in the pathogenesis of asthma. Our specific aims are (1) to investigate the role of Plg-RKT in CCL2 synthesis in vivo and its impact on Plg-RKT-dependent mononuclear cell recruitment and (2) to examine the role of Plg-RKT in the pathogenesis of asthma. We will use Plg-RKT deficient mice and mice over-expressing Plg-RKT to test whether plasmino(ogen)/Plg-RKT-dependent CCL2 up-regulation in vivo is PAR-1- dependent. We will use single cell RNA sequencing to identify cell types responsible for Plg-RKT-dependent stimulation of CCL2 expression and we will determine whether exogenously added CCL2 can rescue the impairment in macrophage recruitment in Plg-RKT-/- mice. We will investigate the role of Plg-RKT in inflammation in ovalbumin-induced asthma and determine whether Plg-RKT regulates airway hyper-responsiveness (AHR). We expect that accomplishment of our specific aims will establish Plg-RKT as a pivotal regulator of the inflammatory response via regulation of expression of the key chemoattractant, CCL2, and provide fundamental insights into how mononuclear cell recruitment is regulated.