1. MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis
Oncotarget, Vol. 6, No. 30
September 10, 2015
IF:6.359
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2. miR-146a Express within the intestines
Barrier gene expression in the intestines
Th17 and Treg populations within the lamina propria
Germinal center reactions in the Peyer’s Patch
DSS-induced colitis
Patients with ulcerative colitis
miR-146a
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3. Inflammatory bowel disease (IBD) Dextran sodium sulfate （DSS）
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Inflammatory bowel disease (IBD)
Dextran sodium sulfate （DSS）
Lamina propria (LP)
Peyer’s Patch (PP)
Germinal center (GC)
Crohn’s disease (CD)
Ulcerative colitis (UC)
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4. 1. miR-146a is expressed within the intestines
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1. miR-146a is expressed within the intestines
TLR/NFκB signaling miRNA-146a
qRT-PCR
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miR-146a is expressed in a variety of intestinal tissues, primarily within cells of the hematopoietic lineage， and this occurs in a microbiota-independent manner.
CD45 cell sorting
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6. 2. miR-146a represses barrier gene expression in the intestines
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2. miR-146a represses barrier gene expression in the intestines
sequencing
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miR-146a functions to repress genes involved in intestinal barrier function and immunoprotective inflammation.
targetscan
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IPA software
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miR-146a-/- mice have enhanced barrier function within their intestinal tract through a mechanism involving enhanced MyD88 signaling.
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3. miR-146a constrains Th17 and Treg populations within the lamina propria
LP isolation
Flow cytometric
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12. miR-146a is playing an immunomodulatory role to
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miR-146a is playing an immunomodulatory role to
shape the intestinal immune landscape.
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13. Peyer’s patch isolation Flow cytometric
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4. miR-146a constrains germinal center reactions in the Peyer’s Patch
Peyer’s patch isolation
Flow cytometric
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14. (Inducible T-cell costimulator)
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(Inducible T-cell costimulator)
Flow cytometry
Stain with fluorescent antibodie ICOS
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miR-146a-/- mice have increased Tfh and GC B cells within the intestine, correlating with elevated T cell ICOS expression and IgA levels.
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17. 5. miR-146a-/- mice are resistant to DSS-induced colitis
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5. miR-146a-/- mice are resistant to DSS-induced colitis
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H&E staining
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miR-146a decreases intestinal barrier function resulting in elevated DSS colitis severity.
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Bone marrow reconstitutions
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21. 6. miR-146a is overexpressed in patients with ulcerative colitis
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6. miR-146a is overexpressed in patients with ulcerative colitis
Higher miR-146a levels correlate with UC, and further investigation may distinguish the severity of disease and/or development of colorectal cancer (CRC) as a result of UC.
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Discussion
miR-146a-/- mice appear to be protected from DSS colitis through a mechanism involving enhanced TLR/MyD88 and IFN/Stat1 signaling.
miR-146a targets identified in RNA-Seq experiment, such as ICOS function in Tfh cells, also appear to be involved
miR-146a acts as a negative regulator of T cell intrinsic TLR/MyD88 signaling that triggers increased Tfh and GC B cell responses, luminal IgA prodction and intestinal health.
miRNA-146a is enriched in cells of hematopoietic lineage，it plays a required role in the hematopoietic compartment.
miR-146a has evolved to play a negative regulatory role during at least some forms of colitis
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Conclusion: our data describe a role for miR-146a in constraining intestinal barrier function, a process that alters gut homeostasis and enhances at least some forms of intestinal disease in mice.
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24. Thanks for your attention
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The end
Thanks for your attention
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