Abstract
Abstract Chemokines plays a crucial role in the migration of leukocytes, which are involved in immune and inflammatory reactions with their receptors. To find novel chemotactic cytokines, we carried out genome-wide bioinformatics analysis and PBMC chemoattractant platform screen. Seven novel potential chemotactic cytokines were picked up, one of them was PC3-secreted microprotein (PSMP). The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, lymphocytes and THP-1 cells. CCR2 was identified as a high-affinity receptor for PSMP by in vitro chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays. Furthermore, we found that PSMP was extensively expressed at low levels in normal human tissues, but was significantly up-regulated in intestinal biopsies from patients with inflammatory bowel disease and mouse DSS-induced colitic tissue in the early stage prior to IL-6, TNF-α and CCL2 up-regulation. Moreover, the results showed that PSMP triggered inflammatory Ly6ChiCCR2+ monocyte migration from the circulation into the lamina propria in a CCR2-dependent manner and promoted the progression of inflammation. A PSMP neutralizing monoclonal antibody significantly mollified inflammation in a mouse DSS colitis model. Taken together, our study provides the first evidence that PSMP is a novel chemotactic cytokines whose receptor is CCR2 and PSMP plays a vital and irreplaceable role in triggering and promoting DSS colitis. Our finding not only reveals the function and regulating mechanism of PSMP, but also provides a promising therapeutic strategy for treating inflammatory bowel disease.
Published Version
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