Presentation Title

Myeloid Cell SOCS3 is Critical for Regulating the Pathogenesis of Dextran Sulfate Sodium (DSS)-induced Colitis

Faculty Mentor

Etty N. Benveniste, Hongwei Qin

Start Date

17-11-2018 12:30 PM

End Date

17-11-2018 2:30 PM

Location

HARBESON 44

Session

POSTER 2

Type of Presentation

Poster

Subject Area

health_nutrition_clinical_science

Abstract

Inflammatory Bowel Diseases (IBDs), including ulcerative colitis and Crohn's disease, are chronic relapsing disorders of the gastrointestinal tract. These disorders play a critical role in the pathogenesis of IBD because macrophage and T cell activation levels are abnormal and imbalanced. Dextran sodium sulfate (DSS)-induced epithelial damage is one of the most widely used models in IBD research. A key component of pathological conditions such as IBDs is the dysregulation of JAK/STAT. In this model, we examine the importance of negative regulating proteins in this pathway such as Suppressors Of Cytokine Signaling (SOCS). SOCS3, in particular, is critical for the inhibition of STAT3 activation. Previous studies have shown that SOCS3 is critical for the polarization of pro-inflammatory macrophages, which contribute to inflammatory responses in Multiple Sclerosis and Parkinson’s Disease. To better understand the function of myeloid cell SOCS3 in the pathogenesis of colitis, mice with SOCS3 deletion in myeloid cells (SOCS3ΔLysM) were utilized in a DSS-induced colitis model. My results indicate that macrophages from SOCS3ΔLysM mice have hyper-activation of STAT1 and STAT3 and enhanced expression of pro-inflammatory molecules, including IL-12, iNOS, CD40, and CD80 compared to cells from SOCS3fl/fl mice. A later part of my data suggests that the SOCS3ΔLysM mice may also have higher activation levels in the dendritic cells, possibly due to the fact that the deficient group possessed a larger myeloid cell population. SOCS3 deficiency in myeloid cells leads to more severe DSS-induced colitis, which correlates with increasing immune cell infiltration in the colon and increased frequency of T cells and macrophages in the spleen. Thus, SOCS3 expression in myeloid cells is critical for regulating the pathogenesis of colitis. My studies suggest that the JAK/STAT pathway plays important roles in the activation of macrophages and pathogenesis of colitis.

Summary of research results to be presented

Using both the SOCS3fl/fl, the wildtype control, and SOCS3DLysMCre, the gene knockout group, I have concluded that SOCS3 deficiency in myeloid cells leads to more severe colitis induced by DSS. A portion of this data was obtained from the seventh day of treatment. Later on, due to complications, we repeated the disease model but obtained data from the fifth day of treatment. According to the data from day 7, the deficiency of the SOCS3 gene in myeloid cells exacerbates epithelial damage as indicated by histology. I observed drastic changes in the anatomical structure of the tissue in both groups of mice, but SOCS3 deficient mice also had increased colonic myeloid cell infiltration. This is consistent with the colon lengths and spleen weights observed on the seventh day, revealing that shorter colon length and larger spleen weight corresponded to increased severity of DSS-induced colitis and indicated enhanced inflammation. However, we concluded that the disease had progressed too far by the seventh day of treatment, potentially masking any significant differences we could have seen. Therefore, we sacrificed the mice on the fifth day of treatment and ran flow cytometry. The SOCS3 deficient group revealed to have a higher CD45+CD11b+ myeloid cell population and higher levels of CD40 in colonic dendritic cells. Lastly, I used the fecal samples of both phenotypes to detect Lipocalin 2 (Lcn2) levels, notoriously prominent in patients with IBDS, where the SOCS3 deficient group had significantly higher Lcn2 levels.

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Nov 17th, 12:30 PM Nov 17th, 2:30 PM

Myeloid Cell SOCS3 is Critical for Regulating the Pathogenesis of Dextran Sulfate Sodium (DSS)-induced Colitis

HARBESON 44

Inflammatory Bowel Diseases (IBDs), including ulcerative colitis and Crohn's disease, are chronic relapsing disorders of the gastrointestinal tract. These disorders play a critical role in the pathogenesis of IBD because macrophage and T cell activation levels are abnormal and imbalanced. Dextran sodium sulfate (DSS)-induced epithelial damage is one of the most widely used models in IBD research. A key component of pathological conditions such as IBDs is the dysregulation of JAK/STAT. In this model, we examine the importance of negative regulating proteins in this pathway such as Suppressors Of Cytokine Signaling (SOCS). SOCS3, in particular, is critical for the inhibition of STAT3 activation. Previous studies have shown that SOCS3 is critical for the polarization of pro-inflammatory macrophages, which contribute to inflammatory responses in Multiple Sclerosis and Parkinson’s Disease. To better understand the function of myeloid cell SOCS3 in the pathogenesis of colitis, mice with SOCS3 deletion in myeloid cells (SOCS3ΔLysM) were utilized in a DSS-induced colitis model. My results indicate that macrophages from SOCS3ΔLysM mice have hyper-activation of STAT1 and STAT3 and enhanced expression of pro-inflammatory molecules, including IL-12, iNOS, CD40, and CD80 compared to cells from SOCS3fl/fl mice. A later part of my data suggests that the SOCS3ΔLysM mice may also have higher activation levels in the dendritic cells, possibly due to the fact that the deficient group possessed a larger myeloid cell population. SOCS3 deficiency in myeloid cells leads to more severe DSS-induced colitis, which correlates with increasing immune cell infiltration in the colon and increased frequency of T cells and macrophages in the spleen. Thus, SOCS3 expression in myeloid cells is critical for regulating the pathogenesis of colitis. My studies suggest that the JAK/STAT pathway plays important roles in the activation of macrophages and pathogenesis of colitis.