Novel cysteinyl leukotriene receptor signaling in regulating cellular, and molecular events in lung inflammation

Project summary: Cysteinyl leukotrienes (cys-LTs; LTC4, LTD4, and LTE4) play an important role in asthma, allergy, and inflammatory bowel diseases via their receptors, CysLT1R and CysLT2R. However, the role of cys-LTs in regulating the inflammatory and proliferative phenotypes of macrophages (MФ) or their role in MФ-mediated lung inflammation is not well defined. Our preliminary work revealed a previously unidentified role for CysLT1R in balancing MФs’ inflammatory potential, metabolic function, and proliferation in vitro, and a role in driving LPS- mediated lung inflammation in vivo. Based on these findings, we hypothesize that the presence of CysLT1R drives the inflammatory state of MФs and lung inflammation in response to LPS. Further, since CysLT1R and CysLT2R antagonize each other, CysLT1R may act as a molecular brake for MФ hyper-proliferation via binding to and inhibiting CysLT2R. We propose to test this hypothesis in three aims. In Aim 1, we will determine the mechanistic aspects of how CysLT1R promotes the hyper-inflammatory MФ phenotype in vitro and analyze how CysLT1R influences the resident and recruited immune population in the lung in response to acute lung injury (ALI). In Aim 2, we will elucidate how CysLT1R suppresses MФ proliferation, and metabolism, and we will explore its antagonism towards CysLT2R in deciding the MФ activation state. Finally, in Aim 3, we will determine the pathophysiological significance of myeloid CysLT1R signaling in mediating lung inflammation in murine ALI models. Further, we will explore the therapeutic potential of blocking CysLT1R using MK571/Singulair, an FDA- approved asthma drug. Although a few reports have suggested the benefits of Singulair in reducing pulmonary inflammation during LPS-ALI and COVID-19, neither the mechanistic aspects, nor its prophylaxis vs therapeutic effect on all ALI parameters, were previously addressed. The successful completion of our project will unravel the previously unknown unique roles of CysLTR in influencing MФ function and its role in lung inflammation/injury.