A ROLE OF NEURONAL PENTRAXIN 2 IN REGULATING PRO-INFLAMMATORY MACROPHAGES IN ULCERATIVE COLITIS

Abstract Significance Inflammatory bowel disease (IBD) is chronic inflammation in the gastrointestinal tract with unknown etiology, including ulcerative colitis (UC). While there are treatments available for patients with IBD, the therapies often fail and the disease relapses, outlining the need for better therapies. Limited studies suggest an association of elevated serum levels of Neuronal Pentraxin 2 (NPTX2), a neuronal protein expressed primarily by excitatory neurons in the brain, with an increased incidence of IBD and inflammation, raising the question of its role in the development of IBD. METHODS Dextran Sodium Sulfate (DSS) was used to induce UC in NPTX2-/- and wild-type (WT) mice. Disease score was evaluated using body weight loss, rectal bleeding, diarrhea, and overall disease index. NPTX2 mRNA levels from the colon tissue of patients with IBD or healthy donors were quantified using RT-qPCR. Nanostring GeoMx spatial analysis was used to identify the cell type in which NPTX2 is expressed in patient tissue with UC and healthy controls. Ex vivo culturing utilizing human- and murine-derived immune cells were done to further determine the roles of NPTX2 in immune cell development and their functions. RESULTS Compared to WT siblings, NPTX2-/- mice have significantly less UC symptoms induced by DSS. Elevated mRNA levels of NPTX2 were detected in the colon mucosa of patients with UC compared to healthy donors. Spatial proteomics revealed NPTX2 expression in the macrophages of patients with UC. MCSF-induced differentiation and chemical-induced activation of human and murine monocytes led to an increase in NPTX2 expression. Moreover, bone marrow-derived monocytes from NPTX2-/- mice have impaired macrophage differentiation and activation towards a pro-inflammatory lineage compared monocytes from wild-type siblings. Lastly, although T cells do not express NPTX2 and are not affected by the NPTX2 knockout, stimulation with extracellular NPTX2 pushed CD4+ T cells towards a pro-inflammatory phenotype, potentially Th1, Th2, and Th17. CONCLUSIONS NPTX2 promotes UC development, which can be attenuated by NPTX2 genetic depletion in mice. We discovered that NPTX2 is expressed in UC-associated macrophages and regulates the activation of pro-inflammatory macrophages. Lastly, our findings suggest NPTX2 may also play a role in T cell functions, either directly via macrophage-secreted NPTX2 in a paracrine fashion, or via regulating macrophage biology and, in turn, affects macrophage-T cell interactions. Future directions include determining the mechanism by which NPTX2 regulates macrophage and T cell functions and developing a clinically relevant therapy strategy to block NPTX2 for treating patients with UC.