1765-P: Inhibition of NLRP3 Inflammasome Activation and Reduction in T-Cell Migration Are Key Mechanisms by Which PAHSAs Protect against Type 1 Diabetes

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are bioactive lipids with anti-inflammatory and anti-diabetic effects. PAHSAs markedly reduce the incidence and delay the onset of autoimmune T1D in NOD mice. PAHSAs attenuate autoimmune responses by lowering mature T helper cell activation and B cell number and increasing regulatory T cell activity in the islets of NOD mice. Toll-like receptors and NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome pathways play an essential role in T1D pathogenesis. NLRP3 is critical for inducing expression of chemokines and their receptors which stimulate pathogenic T cell migration into islets. Here, we aimed to determine the mechanisms by which PAHSAs attenuate immune responses to prevent T1D. Results: Adoptive transfer of splenocytes from PAHSA-treated NOD mice delays and attenuates T1D incidence in immunodeficient NOD.SCID mice. These effects are associated with decreased expression of NLRP3 inflammasome components by 25-55% and chemokines by 60-70% without altering chemokine receptor expression in immune cells isolated from PAHSA-treated NOD mouse islets. In human islets from normal and type 2 diabetic donors, clonal pancreatic β-cells (MIN6 cells) and bone marrow-derived macrophages, PAHSAs attenuate pro-inflammatory cytokine and chemokine gene expression and secretion in response to LPS or Nigericin (NLRP3 inflammasome activator). In co-culture studies of MIN6 cells and CD4+ T cells, PAHSAs attenuate LPS and Nigericin-induced CD4+ T cell migration by 65%. Conclusions: PAHSAs’ protective effects against T1D can be conferred by transfer of immune cells from PAHSA-treated mice. Inhibition of NLRP3 inflammasome activation and T cell migration into islets are key mechanisms by which PAHSAs protect islets from immune-mediated attack. Thus, PAHSAs may serve as therapeutic agents to prevent and/or treat T1D. Disclosure I. Syed: None. V.G. Magupalli: None. P. Aryal: Employee; Cellarity. A. Santoro: None. D. Siegel: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc. Funding NIH K01 DK118041 (IS).Joslin Pilot & Feasibility Grant P30 DK046200 (IS).NIH R01 DK106210 (BBK).JPB Foundation (BBK).