Autotaxin determines colitis severity in mice and is secreted by B cells in the colon

Abstract

Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1−/− and µMT mice, suggesting B cells as a major ATX‐producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.—Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El‐Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon. FASEB J. 33, 3623–3635 (2019). http://www.fasebj.org

Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer

“…Pharmacological inhibition of ATX mitigated disease activity in DSS-induced model of IBD [69]. Consistently, deletion of Enpp2 gene decreased disease severity in both acute and chronic colitis induced by DSS with significant decreases in mucosal damage and inflammation [57].…”

“…ATX promotes lymphocyte-HEV interactions by generating LPA locally, while ATX inhibition abolishes T cell entry into lymph node by arresting the transendothelial migration of T cells [73,74]. In keeping with these studies, there was a significant decrease in CD45 + or CD3 + cells in DSS-treated Enpp2 −/− mice [57].…”

“…In contrast to the previous study [55], we found that deletion of ATX with tamoxifen (TAM) in adult Enpp2 f/f ;R26CreERT mice resulted in significant body weight loss. Most of TAM-treated mice gradually recovered body weights over the next several days, but about of a quarter of mice failed to recover [57]. There was evidence of increased inflammation with immune cell infiltration and elevated levels of TNF-α and INF-γ.…”

“…Hozumi et al [69] observed that ATX mRNA levels are considerably elevated in inflamed mucosa from CD and UC patients. Similarly, ATX mRNA expression is elevated in dextran sodium sulfate (DSS)-induced rodent model of colitis and SAMP1/Fc mice, a mouse model of CD-like ileitis [57,69,70]. Pharmacological inhibition of ATX mitigated disease activity in DSS-induced model of IBD [69].…”

Malnutrition Accelerates Colorectal Cancer Progression through Macrophage Activated by B Cells Immune via Gut Microbiota

“…Meanwhile, tumor macroenvironment could affect the differentiation, function and distribution of B lymphocytes, switching B cells to pro-, rather than anti-, tumoral phenotype [20]. B cells could aggravate the in ammatory response and promote the colitis to colorectal cancer [21,22]. This raise the question -did the malnutrition affect the B cells in ltration in CRC or did B cells worsen the malnutrition status?…”