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Distinct compartmentalization of NF-?B activity in crypt and crypt-denuded lamina propria precedes and accompanies hyperplasia and/or colitis following bacterial infection.

ABSTRACT: Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis depending upon the genetic background. Utilizing C. rodentium-induced TMCH in C3H/HeNHsd inbred mice, we observed significant crypt hyperplasia on days 3 and 7 preceding active colitis. NF-?B activity in the crypt-denuded lamina propria (CLP) increased within 24 h postinfection, followed by its activation in the crypts at day 3, which peaked by day 7. Increases in interleukin-?1 (IL-1?), IL-12(p40), and macrophage inflammatory protein 1? (MIP-1?) paralleled NF-?B activation, while increases in IL-1?/?, IL-6/IL-12(p40)/granulocyte colony-stimulating factor (G-CSF)/keratinocyte-derived chemokine (KC)/monocyte chemotactic protein 1 (MCP-1), and MIP-1? followed NF-?B activation leading to significant recruitment of neutrophils to the colonic mucosa and increased colonic myeloperoxidase (MPO) activity. Phosphorylation of the crypt cellular and nuclear p65 subunit at serines 276 and 536 led to functional NF-?B activation that facilitated expression of its downstream target, CXCL-1/KC, during TMCH. Distinct compartmentalization of phosphorylated extracellular signal-regulated kinase 1 and 2 ([ERK1/2] Thr(180)/Tyr(182)) and p38 (Thr(202)/Tyr(204)) in the CLP preceded increases in the crypts. Inhibition of ERK1/2 and p38 suppressed NF-?B activity in both crypts and the CLP. Dietary administration of 6% pectin or 4% curcumin in C. rodentium-infected mice also inhibited NF-?B activity and blocked CD3, F4/80, IL-1?/?, G-CSF/MCP-1/KC, and MPO activity in the CLP while not affecting NF-?B activity in the crypts. Thus, distinct compartmentalization of NF-?B activity in the crypts and the CLP regulates crypt hyperplasia and/or colitis, and dietary intervention may be a novel strategy to modulate NF-?B-dependent protective immunity to facilitate crypt regeneration following C. rodentium-induced pathogenesis.

SUBMITTER: Chandrakesan P

PROVIDER: S-EPMC3264290 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Distinct compartmentalization of NF-κB activity in crypt and crypt-denuded lamina propria precedes and accompanies hyperplasia and/or colitis following bacterial infection.

Chandrakesan Parthasarathy P Ahmed Ishfaq I Chinthalapally Anisha A Singh Pomila P Awasthi Shanjana S Anant Shrikant S Umar Shahid S

Infection and immunity 20111205 2

Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis depending upon the genetic background. Utilizing C. rodentium-induced TMCH in C3H/HeNHsd inbred mice, we observed significant crypt hyperplasia on days 3 and 7 preceding active colitis. NF-κB activity in the crypt-denuded lamina propria (CLP) increased within 24 h postinfection, followed by its activation in the crypts at day 3, which peaked by day 7. Increases in inter ...[more]

PMID: 22144489

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Project description:BackgroundUlcerative colitis (UC) is a severe threat to humans worldwide. Single-cell RNA sequencing (scRNA-seq) can be used to screen gene expression patterns of each cell in the intestine, provide new insights into the potential mechanism of UC, and analyze the development of immune cell changes. These findings can provide new ideas for the diagnosis and treatment of intestinal diseases. In this study, bioinformatics analysis combined with experiments applied in dextran sulfate sodium (DSS)-induced colitis mice was used to explore new diagnostic genes for UC and their potential relationship with immune cells.MethodsWe downloaded microarray datasets (GSE75214, GSE87473, GSE92415) from the Gene Expression Omnibus and used these datasets to screen differentially expressed genes (DEGs) and conduct Weighted Gene Co-expression Network Analysis (WGCNA) after quality control. The hub genes were screened, and ROC curves were drawn to verify the reliability of the results in both training set (GSE75214, GSE87473, GSE92415) and validation cohort (GSE87466). Also, we explored the relation of diagnostic genes and immune cells by CIBERSORT algorithm and single-cell analysis. Finally, the expression of hub genes and their relation with immune cells were verified in DSS-induced colitis mice.ResultsDiagnostic genes (ANXA5, MMP7, NR1H4, CYP3A4, ABCG2) were identified. In addition, we found these five genes firmly related to immune infiltration. The DSS-induced colitis mice confirm that the expression of ANXA5 mainly increased in the intestinal macrophages and had a strong negative correlation with M2 macrophages, which indicated its possible influence on the polarization of macrophages in UC patients.ConclusionWe identified ANXA5, MMP7, NR1H4, CYP3A4, and ABCG2 as diagnostic genes of UC that are closely related to immune infiltration and ANXA5 maintains a negative correlation with M2 macrophages which indicated its possible influence on the polarization of macrophage in UC patients.

Dataset Information

Distinct compartmentalization of NF-?B activity in crypt and crypt-denuded lamina propria precedes and accompanies hyperplasia and/or colitis following bacterial infection.

Publications

Distinct compartmentalization of NF-κB activity in crypt and crypt-denuded lamina propria precedes and accompanies hyperplasia and/or colitis following bacterial infection.

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