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Isolation and Characterization of Dendritic Cells and Macrophages from the Mouse Intestine
Published on: May 21, 2012
MKL1 expressed in macrophages contributes to the development of murine colitis
Jianbo An1, Takashi Nagaishi2, Taro Watabe2
1Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
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.
Insights
Megakaryoblastic leukaemia 1 (Mkl1) gene overexpression in macrophages exacerbates inflammatory bowel disease (IBD) development. Mkl1 dysregulates macrophage function, increasing colitis susceptibility and suggesting Mkl1 as a therapeutic target.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Megakaryoblastic leukaemia 1 (Mkl1) gene deficiency reduces dextran sulphate sodium (DSS)-induced colitis severity, suggesting a pathological role in inflammatory bowel disease (IBD).
- Mkl1 expression is elevated in colonic lamina propria macrophages (LPMac) during DSS-induced colitis.
Purpose of the Study:
- To investigate the role of macrophage-specific Mkl1 in the pathogenesis of colitis.
- To establish and analyze a transgenic mouse model overexpressing human MKL1 (MKL1-Tg) in monocytes/macrophages.
Main Methods:
- Generation of MKL1-Tg mice overexpressing human MKL1 in myeloid cells.
- Flow cytometry and quantitative RT-PCR to analyze LPMac populations and inflammatory phenotypes.
- Assessment of DSS-induced colitis susceptibility in MKL1-Tg and control mice.
Main Results:
- MKL1-Tg mice exhibited spontaneous colon shortening and rectal prolapse.
- LPMac populations were reduced in MKL1-Tg mice, displaying impaired anti-inflammatory properties.
- Bone marrow-derived macrophages from MKL1-Tg mice showed a pro-inflammatory M1 polarization bias.
- MKL1-Tg mice demonstrated increased susceptibility to DSS-induced colitis.
Conclusions:
- Mkl1 plays a crucial role in colitis development by regulating macrophage function.
- Mkl1-induced alterations in macrophage phenotype and function contribute to IBD pathogenesis.
- Mkl1 represents a potential therapeutic target for IBD prevention and treatment.
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