PROJECT SUMMARY Extensive work has implicated human resistin (Hresistin) and its rodent correlate resistin-like molecule (RELM)- α in inflammatory mechanisms of pulmonary hypertension (PH). Elevated levels of Hresistin in the lungs of idiopathic PAH and Scleroderma PH patients1,2 correlate with the disease severity of PH and predict mortality.3 Rodent models of PH show RELMα is critical to PH remodeling of the lung vasculature and right heart.3-7 We reported Bruton’s Tyrosine Kinase (BTK) as a binding partner of RELMα/Hresistin,8 and mediator of chemokine activities of RELMα/Hresistin in myeloid cells.1,8 We also reported that, Hresistin/RELMα initiates the inflammatory response to injury at PH onset, through activating damage-associated molecular pattern (DAMP) pathway high-mobility group box-1 (HMGB1).1,4,9 However, it is unclear how Hresistin/RELMα’s diverse inflammatory effects are integrated or how they amplify and sustain inflammation to induce vascular remodeling over time. The NLRP3 inflammasome was recently suggested to be central to the vascular inflammation in PH.10 It mediates the innate response to injury and is associated with the transition to adaptive immunity. Here, we intend to demonstrate the novel concept that Hresistin/RELMα is a critical regulator of the priming and activation stages of the NLRP3 inflammasome. Our preliminary data suggests the hypothesis that Hresistin/RELM ritical α is c to both NLRP3 priming (via HMGB1)11 and NLRP3 activation (via BTK) and production of IL-1β and IL-18 (via critical BTK12 phosphorylation of four specific NLRP3 tyrosine residues) in both macrophages and B cells, leading to pulmonary vascular remodeling and PH. It suggests a major and novel role for Hresistin/RELMα in engaging the NLRP3 inflammasome in the innate immune response to injury and to a sustaining adaptive immune response in the long-term remodeling associated with PH. We address this hypothesis in two aims: Aim 1: To dissect and prove the detailed mechanism of how Hresistin regulates NLRP3 inflammasome in inflammatory cells; Aim 2: To investigate the contribution of Hresistin- regulated inflammasome to vascular remodeling and PH.