Abstract
Mice deficient in the megakaryoblastic leukaemia 1 (Mkl1) gene experience less severe dextran sulphate sodium (DSS)-induced colitis, implying that Mkl1 plays a pathological role in inflammatory bowel disease (IBD). However, the contribution of Mkl1 to the development of colitis remains to be elucidated. The expression of Mkl1 is higher in the colonic lamina propria macrophages (LPMac) of DSS-treated mice than in those of control mice. Therefore, we established a transgenic mouse line that overexpresses human MKL1 (MKL1-Tg) specifically in cells of the monocyte/macrophage lineage, in order to investigate the potential role of macrophage MKL1 in the pathogenesis of colitis. MKL1-Tg mice displayed spontaneous colon shortening and rectal prolapse. Flow cytometric and quantitative RT-PCR analyses revealed that, in MKL1-Tg mice compared to littermate controls, the population of LPMac was decreased and had an altered inflammatory phenotype indicative of impaired anti-inflammatory properties, whereas bone marrow-derived macrophages from MKL1-Tg mice skewed towards M1 polarisation. In addition, MKL1-Tg mice had higher susceptibility to DSS-induced colitis than their littermate controls. These observations indicated that MKL1 crucially contributes to the development of colitis via the regulation of the function of macrophages, suggesting that it may be a potential therapeutic target for the prevention of IBD.
Highlights
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterised by chronic, progressive inflammation of the gastrointestinal tract
We observed that mice that received 3% dextran sulphate sodium (DSS) had a decreased proportion of lamina propria macrophages (LPMac) accompanied by a significant increase in the proportion of lamina propria monocytes (LPMo) (Fig. 1A and Supplementary Fig. S1)
Murine DSS-induced colitis is a classical model for studying the pathogenesis of IBD13, and megakaryoblastic leukaemia 1 (Mkl1)-knockout mice are known to develop DSS-induced colitis of mitigated severity[7]
Summary
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterised by chronic, progressive inflammation of the gastrointestinal tract. MKL1 mediates the upregulation of pro-inflammatory cytokines in response to inflammatory stimuli[7]. Murine experimental colitis is less severe in Mkl1-knockout mice[7], suggesting the involvement of Mkl[1] in IBD. Given that the immune system plays a central role in IBD, it is likely that MKL1 in leukocytes contributes to the development of colitis. We found that the expression of Mkl[1] was significantly elevated in LPMac, but not in whole colon tissue, in the setting of murine experimental colitis, compared to that in the steady state, suggesting an important role for MKL1 in macrophages in the development of IBD. We found that MKL1 overexpression was associated with skewed macrophage polarisation, which may underlie the molecular pathogenesis of IBD in MKL1-Tg mice
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