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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
P38α deficiency in macrophages ameliorates murine experimental colitis by regulating inflammation and immune process
Wei Chen1, Rui Liang2, Youcai Yi1
1Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Introduction:
P38α is a mitogen-activated protein kinase (MAPK) that mediates inflammatory responses. P38α alterations have been associated with the inflammation-related diseases. However, the role of macrophages-derived p38α in dextran sulfate sodium (DSS)-induced murine experimental colitis remains unclear.
Objectives:
We characterized the role of macrophages-derived p38α in DSS-induced colitis.
Methods:
The expression of macrophage-derived p38α in human colitis and normal tissues was measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Macrophage-specific p38α knockout (p38αΔMφ) and wild type (WT) mice administrated by 3% DSS were used to establish experimental colitis. The alterations in inflammatory cytokines, intestinal epithelial barrier, cell proliferation and cell apoptosis between p38αΔMφ and WT groups were determined by IHC, immunofluorescence (IF), TdT-mediated dUTP Nick-End Labeling (TUNEL) and Western blot analyses. The enriched pathways between p38αΔMφ and WT groups were identified by RNA-seq and KEGG analysis. SB203580 and BIRB796 as the p38 MAPK inhibitors were used to treat DSS-induced colitis.
Results:
p38α was co-localized with CD68 in the cytoplasm and their co-expression indicated an increased level in colitis tissues as compared with the normal tissues. P38α deficiency in macrophages was sufficient to suppress the exacerbated clinical symptoms and inflammation responses in experimental colitis, followed by reducing cytokine release, increasing MUC-2 and Claudin-2 secretion and promoting colonic mucosa repair. Further investigations validated that the immune process-related factors such as Lgals9, Rtp4, Ddx60, Nlrp1b, Hsh2d, Oas2 and Oas3 were upregulated in colon tissues from p38αΔMφ group as compared with the WT group. Inhibition of p38 MAPK attenuated DSS-induced colitis.
Conclusion:
Our findings demonstrated that p38α deficiency in macrophages ameliorated murine experimental colitis by regulating inflammation and immune process.
Insights
Macrophages-derived p38α exacerbates experimental colitis. Its deficiency ameliorates disease by regulating inflammation and immune processes, offering therapeutic potential for inflammatory bowel disease.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- P38α (mitogen-activated protein kinase) is implicated in inflammatory responses and associated diseases.
- The specific role of macrophage-derived p38α in dextran sulfate sodium (DSS)-induced colitis remains largely uncharacterized.
Purpose of the Study:
- To elucidate the function of macrophage-derived p38α in DSS-induced murine experimental colitis.
- To investigate the molecular mechanisms underlying p38α's role in colitis pathogenesis.
Main Methods:
- Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to assess p38α expression in human tissues.
- Macrophage-specific p38α knockout (p38αΔMφ) and wild-type (WT) mice models of DSS-induced colitis.
- Analysis of inflammatory cytokines, intestinal barrier integrity, cell proliferation, and apoptosis using IHC, immunofluorescence (IF), TUNEL, and Western blot.
- RNA-sequencing (RNA-seq) and KEGG pathway analysis to identify enriched pathways.
- Treatment with p38 MAPK inhibitors (SB203580 and BIRB796).
Main Results:
- Macrophage-derived p38α expression was elevated in human colitis tissues.
- Macrophage-specific p38α deficiency significantly suppressed DSS-induced colitis symptoms and inflammation.
- Reduced cytokine release, enhanced MUC-2 and Claudin-2 secretion, and promoted colonic mucosal repair were observed in p38αΔMφ mice.
- Upregulation of immune process-related factors (e.g., Lgals9, Rtp4, Ddx60) was noted in p38α-deficient mice.
- Pharmacological inhibition of p38 MAPK attenuated DSS-induced colitis.
Conclusions:
- Macrophage-derived p38α plays a critical role in exacerbating experimental colitis.
- Targeting macrophage-derived p38α ameliorates colitis by modulating inflammatory and immune responses.
- These findings highlight p38α as a potential therapeutic target for inflammatory bowel diseases.
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