NOVEL FUNCTION OF MYELOID METHYLTRANSFERASE SMYD5 IN INFLAMMATORY BOWEL DISEASE PROGRESSION

Background and Aims SET and MYND domain-containing protein 5 (SMYD5) is a lysine methyltransferase and broadly expressed across various tissues, including immune cells. However, the myeloid SMYD5 in inflammatory bowel disease is entirely unknown. Here, we interrogated the role of SMYD5 in IBD pathogenesis and progression. METHODS Colitis was induced in myeloid-specific Smyd5 knockout (Smyd5fl/flLyz2+/-) and floxed control (Smyd5fl/fl) mice through DSS administration in drinking water for 7 days followed by regulator drinking water for 1 day. The induction of colitis was evaluated by measuring relative body weight loss, disease activity index, and histological as well as morphological changes in the colon. The infiltration of macrophages and neutrophils was examined by immunohistochemical staining. Smyd5 depletion in the myeloid cells in Smyd5fl/flLyz2+/- mice was confirmed by quantitative real-time PCR (RT-PCR). The formation of neutrophil extracellular traps (NET) was observed by immunofluorescence microscopy in vitro and in vivo. RESULTS Smyd5fl/flLyz2+/- mice administered with DSS displayed a significantly worsened colitis reflected by profound body weight loss and an exaggerated disease activity compared to Smyd5fl/fl mice that received DSS. Meanwhile, Smyd5fl/flLyz2+/- mice receiving DSS exhibited severer tissue damages and immune cell infiltration compared to Smyd5fl/fl mice. In addition, more infiltrated neutrophils were observed in the colon tissues of Smyd5fl/flLyz2+/- mice than in Smyd5fl/fl mice that received DSS. However, the infiltration of macrophages was comparable between these two groups. Moreover, we also observed exaggerated NET formation when Smyd5 was silenced both in vitro and in vivo. CONCLUSION Our findings suggest that SMYD5 depletion in myeloid cells leads to exaggerated disease in acute experimental colitis. Furthermore, these data revealed that SMYD5 might play a critical role in suppressing inflammatory response and could serve as a potential therapeutic target in IBD.