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  • Macrophage populations are prominent in active

    2021-11-25

    Macrophage populations are prominent in active IBD (Strober and James, 1986) as compared to healthy donors. Further, percentages of macrophages are increased in DSS-induced colitis (Grose et al., 2001, Ogawa et al., 2004). IBD is also linked to an influx of neutrophils and depletion of neutrophils by monoclonal Agarose GPG/ME mg has been shown to decrease several parameters of DSS-induced colitis (Natsui et al., 1997). In the present study, we observed increases in macrophages, neutrophils, NK1.1, and NKT cells in the spleens, MLNs, PPs and LP of DSS-induced colitic mice. FAAH-II treatment of colitic mice reversed the increase in number of inflammatory cells to normal levels in spleens, MLNs, PPs and LP. There is increased expression and level of IL-6 and IL-1β in IBD patient systemic and mucosal biopsies (Casini-Raggi et al., 1995, Reimund et al., 1996). Also, IBD patients’ IL-6 serum levels correlate with disease activity (Holtkamp et al., 1995). RANTES has been shown to be elevated in several inflammatory conditions, including lupus, rheumatoid arthritis, and multiple sclerosis (Boiardi et al., 1999, Vila et al., 2007). MCP-1 levels are elevated in experimental models of colitis and in the mucosal tissues of IBD patients (Keates et al., 1997, McCormack et al., 2001, Scheerens et al., 2001). In the present study, we observed significant decreases in both systemic and local colon tissue MCP-1, RANTES, IL-6, and IL-1β in colitic mice treated with FAAH-II as compared to colitic mice given DSS alone. Similarly, we observed a significant increase in systemic anti-inflammatory cytokine IL-10 in the FAAH-II treated group as compared to mice given DSS alone. These results show that reduction of these cytokines and chemokines, from colon site along with increases in systemic anti-inflammatory cytokines, which correlate with the severity of colon inflammation after FAAH-II treatment, can lead to the amelioration of colitis. In the present study, we have demonstrated that FAAH-II inhibitor suppresses several proinflammatory cytokines, which is linked to alterations in the expression of several miRNAs. After FAAH-II treatment, we found changes in expression of 26 miRNAs from MLNs and 217 miRNAs from PPs. Several putative targets of these miRNAs are related to the inflammatory process. After FAAH-II treatment, miR-145-5p, miR-182-p, and miR-200b-5p were increased in the PPs. Based on pathway analysis, they targeted FOXO1 and SMAD2, which are involved in IL-6 induction thereby suggesting how these miRs may down, regulate IL-6. miR-217 has also been shown to downregulate Sirt-1 expression in ethanol-induced fat accumulation in hepatocytes (Yin et al., 2012). Treatment with FAAH-II was followed by decreased miR-217 expression in PPs. Thus, in our study, miR-217 may induce Sirt-1 and provide protection against intestinal inflammation in as much as, we have shown previously that Sirt-1 induction by resveratrol protects mice from gut inflammation (Singh et al., 2010). Also, some of the down regulated miRNAs in MLNs such as miR-146a-5p seen following treatment with FAAH-II may induce more IL-10 or miR-141-3p may induce STAT4 which regulates IL-10, thereby promoting anti-inflammatory cytokines. Significant evidence indicates that microRNAs play a critical role in the pathogenesis and progression of IBD. However, it is not known how alteration in miRNAs expression specifically contributes to IBD pathobiology. Several studies have identified miRNAs that are associated with IBD in intestinal tissues and peripheral blood specimens (Coskun et al., 2012, Wu et al., 2011, Wu et al., 2008). To this end, studies using interleukin-10 knockout (IL-10−/−) mice, a model of chronic intestinal inflammation, have shown selective dysregulation of miRNAs in colon tissue and peripheral blood leukocytes (Schaefer et al., 2011). In the present study, we found an increase in miR-200b-3p after FAAH treatment in PP. This was consistent with the earlier finding of (Zidar et al., 2016) that downregulation of members of the miR-200 family supports the possibility that miR-200 has a role in pathogenesis of fibrosis in IBD. Further, it has also been shown that has-miR-141-3p is upregulated in the rectosigmoid area, as compared to the ascending colon area, of UC patients (Ranjha et al., 2015). This supports our present finding of an increase in miR-141 expression in the MLN after FAAH treatment. Similarly, it has been shown that changes in miR-141 expression in TNBS induced or IL-10-/- colitis models regulate leukocyte infiltration and mediate colitis (Huang et al., 2014). Taken together, our results and those of others clearly support the role of miRNAs in models of acute and experimental colitis.