induction-intestinal-inflammation-adoptive-transfer-cbir1-tcr

Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4<sup>+</sup> T Cells to Immunodeficient Mice

With the increase of incidence, inflammatory bowel diseases (IBD), which are chronic diseases affecting the gastrointestinal tract, impose a considerable ...

University of Texas Medical Branch

university of texas medical branch

Intestinal tissues from patients with inflammatory bowel disease (IBD) and colorectal cancer have increased expression of microRNA-301a (MIR301A) compared with tissues from patients without IBD. We studied the mechanisms of MIR301A in the progression of IBD in human tissues and mice.

MicroRNA 301A Promotes Intestinal Inflammation and Colitis-Associated Cancer Development by Inhibiting BTG1.

Neutrophils are accumulated in inflamed mucosa of IBD and play an important role in the pathogenesis. CD177 is expressed in neutrophils specifically and upregulated during inflammation. However, the role of CD177 neutrophils in pathogenesis of IBD remains elusive.

CD177 neutrophils as functionally activated neutrophils negatively regulate IBD.

Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases.

Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting T1/T17 cell differentiation in patients with inflammatory bowel diseases.

Neutrophils are found to be infiltrated in tumour tissues of patients with colitis-associated cancer (CAC) and colorectal cancer (CRC), and CD177 is mainly expressed in neutrophils. In our study, expression of CD177 in tumour tissues from patients with CAC or CRC was analysed byquantitative real-time polymerase chain reaction, flow cytometry and immunohistochemistry. We recruited 378 patients with CRC, determined CD177 expression in tumours and examined its correlation with clinicopathological features. Moreover, CAC model was induced in wild-type and CD177-/- mice by azoxymethane/dextran sodium sulphate. CD177+ neutrophils were significantly increased in colon tumour tissues from patients with CRC or CAC compared with controls. Expression of CD177 mRNA and percentages of CD177+ neutrophils were also markedly increased in tumour tissues from CRC patients compared with controls. Patients with high density of CD177+ neutrophils had better overall survival and disease-free survival compared with controls. Multivariate analyses revealed that the density of CD177+ neutrophils was an independent factor in predicting overall survival and disease-free survival. Consistently, CD177 depletion aggravated azoxymethane/dextran sodium sulphate-induced CAC in mice. Expression of Ki67 and proliferating cell nuclear antigen was increased in tumour tissues from CD177-/- mice compared with wild-type counterparts. Moreover, CD177-/- neutrophils failed to migrate in response to fMLP[AU: Please expand fMLP, DN, TNM and HIF-1α.] stimulation compared with wild-type controls. Our data indicate that CD177+ neutrophils suppress epithelial cell tumourigenesis and act as an independent factor in predicting the prognosis in patients with CRC. CD177+ neutrophils may serve as a novel therapeutic target in the treatment and predict the prognosis of CAC and CRC.

CD177+ neutrophils suppress epithelial cell tumourigenesis in colitis-associated cancer and predict good prognosis in colorectal cancer.

Rho-associated kinase (ROCK) has been found to be involved in the pathogenesis of a variety of autoimmune diseases, but the role of ROCK in inflammatory bowel disease (IBD) is still elusive. In this study, we demonstrated that the levels of ROCK2, but not ROCK1, activity were significantly upregulated in peripheral blood mononuclear cells (PBMC) and inflamed mucosa from IBD patients using a ROCK activity assay, and that ROCK2 activity in intestinal mucosa was positively correlated with disease severity. Stimulation with TNF markedly upregulated ROCK2 activity in IBD CD4 T cells through NF-κB signaling. Blockade of ROCK2 activity using Slx-2119 significantly suppressed proinflammatory cytokines in inflamed mucosa from IBD patients including IFX-unresponsive CD patients, and inhibited IBD CD4 T cells to differentiate into Th1 and Th17 cells through downregulating phosphorylated Stat1 and Stat3, but promoted Treg cell differentiation through upregulating phosphorylated Stat5. Furthermore, oral administration of Slx-2119 markedly ameliorated intestinal mucosal inflammation in TNBS-induced colitis in mice and decreased proinflammatory cytokines productions in inflamed colon. Our data indicate that ROCK2 plays a critical role in inducing mucosal T cell activation and inflammatory responses in IBD and that inhibition of ROCK2 activity might serve as a novel therapeutic approach in the management of IBD.

Critical role of ROCK2 activity in facilitating mucosal CD4 T cell activation in inflammatory bowel disease.

Innate lymphoid cells (ILCs) and CD4 T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4 T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4 T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4 T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4 T cells and ILCs to maintain intestinal homeostasis.

Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity.

G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4 T cell function to inhibit colitis development.

Tianming Yu

Department of Microbiology and Immunology

University of Texas Medical Branch

Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4⁺ T Cells to Immunodeficient Mice

Tianming Yu

Department of Microbiology and Immunology

University of Texas Medical Branch

Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4+ T Cells to Immunodeficient Mice

Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4⁺ T Cells to Immunodeficient Mice