Systemic hypertension is a leading worldwide cause of morbidity and mortality. Salt-sensitivity is seen in over half of affected individuals with systemic hypertension as well in significant numbers of normotensive individuals at risk for subsequent development of hypertension. The etiology of “essential” hypertension is multifactorial and has been described as a “mosaic”, but numerous studies indicate an important role for both the adaptive and the innate immune systems in mediation of salt-sensitivity by affecting both kidney and vasculature in hypertension development and/or exacerbation. The studies proposed in this application will investigate novel interactions of the myeloid cyclooxygenase (COX)/prostaglandin system with the adaptive immune system and mechanisms by which this interaction can mediate regulation of kidney salt handling and hemodynamic responses to dietary salt. Myeloid cells of the innate immune system, especially macrophages and dendritic cells, are known to be a rich source of prostaglandins. Prostaglandins, and specifically PGE2, can act as immune modulators and affect both macrophage/dendritic cell and T cell function. Cyclooxygenase is the rate limiting step in the synthesis of prostaglandins from arachidonic acid, and cyclooxygenase 2 (COX-2) is the predominant inducible isoform in myeloid cells. We previously found that PGE2 is the predominant prostaglandin produced by COX-2 in kidney myeloid cells (macrophages and dendritic cells), and myeloid COX-2 deficiency leads to a proinflammatory (“M1”) phenotype while COX-2-mediated activation of the PGE2 receptor, PTGER2/EP4, promotes a non- inflammatory, alternatively activated (“M2”) phenotype. Experimental and epidemiologic evidence link inhibition or abnormalities in the cyclooxygenase/prostaglandin system to the pathogenesis or exacerbation of hypertension. Our previous studies demonstrated that COX-2-derived prostaglandins from myeloid cells of the innate immune system are important mediators of kidney salt and water balance. Wild type mice transplanted with COX-2-/- bone marrow exacerbated increases in high salt-induced blood pressure. However, our previous studies did not elucidate the mechanisms mediating these blood pressure alterations. We now find that mice with selective myeloid deletion of COX-2 have increased hypertension and T cell kidney infiltration in response to a high salt diet, but myeloid COX-2-/- mice crossed with mice with the Rag-1 deletion, which lack mature lymphocytes, fail to increase blood pressure. These results indicate a potential role for myeloid COX-2 activity to decrease T cell activation in response to a high salt diet. In the present studies, Aim I will investigate alterations in T cell phenotype in response to myeloid deletion of COX-2 alterations in T cell-mediated increases in kidney sodium reabsorption and/or directly activates kidney sodium transporters. Aim II will determine the role of myeloid COX-2 activity to activate the PD-L...