scholarly journals A188 TARGETING RIPK2 TO TREAT INTESTINAL INFLAMMATION CAUSED BY SHIP DEFICIENCY

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 204-205
Author(s):  
Y Pang ◽  
S Menzies ◽  
S Baksh ◽  
L M Sly
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Vehicle Control ◽  
Wall Thickening ◽  
Immune Cell Infiltration ◽  
Inflammatory Cytokine Production ◽  
Gross Pathology ◽  
Histological Damage

Abstract Background Crohn’s disease (CD) is a form of inflammatory bowel disease characterized by chronic inflammation along the gastrointestinal tract. We have described the SHIP-/- mouse model of CD-like intestinal inflammation. SHIP-/- mice develop spontaneous ileal inflammation that is characterized by villus hyperplasia and disorganization, edema, immune cell infiltration, ulceration, loss of goblet cells, and muscle wall thickening. SHIP deficiency in people with CD has been associated with a more severe and treatment-refractory disease. Interestingly, NOD2 gene variants, which are the most profound genetic associations for CD, are also associated with a more severe CD phenotype. Muramyl dipeptide (MDP) is a molecular associated microbial pattern, which activates the NOD2 signalling pathway. Recently, SHIP has been reported to play a role in the NOD2 pathway by disrupting the downstream interaction between RIPK2 and XIAP required for NOD2-mediated NFκB activation and pro-inflammatory cytokine production. Aims Based on this, we hypothesized that SHIP deficiency contributes to inflammation in CD by increasing NOD2-mediated pro-inflammatory cytokine production. Moreover, RIPK2 inhibitors will block intestinal inflammation caused by SHIP deficiency by blocking RIPK2-XIAP interactions required for NOD2 signalling and resultant pro-inflammatory cytokine production. To test this hypothesis, my aim was to determine the effect of RIPK2 inhibitors on the development of spontaneous intestinal inflammation in SHIP-/- mice. Methods 6 week-old SHIP-/- mice (and SHIP+/+ mice controls) were treated with RIPK2 inhibitors, FCG806791773 or Z1210264067, by intra-pertioneal injections every other day for 2 weeks and compared to SHIP-/- mice treated with 2% DMSO in PBS, as a vehicle control. On Day 14, distal ilea were harvested and gross pathology was assessed. Cross-sections of the ilea were H&E stained to evaluate histological damage based on villi architecture, edema, immune cell infiltration, ulceration, goblet cell loss, and muscle wall thickening. Results As expected, SHIP+/+ mice did not have gut pathology and their healthy gut phenotype was not affected by RIPK2 inhibitors. SHIP-/- mice had ileal inflammation that was evident in gross pathology and in H&E-stained tissue sections. Importantly, SHIP-/- mice treated with RIPK2 inhibitors, FCG806791773 or Z1210264067, had reduced gross pathology compared to vehicle control-treated mice. Z1210264067 treated SHIP-/- mice also had significantly lower histological damage compared to vehicle control-treated SHIP-/- mice. Conclusions RIPK2 inhibitors reduced gross and histopathology in SHIP-/- mice suggesting that RIPK2 inhibitors may be an effective treatment for people with CD, and may be particularly effective in people with CD, who harbor NOD2 risk variants and/or have low SHIP activity. Funding Agencies CCC, CIHR

scholarly journals Ghrelin and vascular protection

2019 ◽  
Vol 1 (1) ◽  
pp. H97-H102
Author(s):  
James T Pearson ◽  
Mikiyasu Shirai ◽  
Vijayakumar Sukumaran ◽  
Cheng-Kun Du ◽  
Hirotsugu Tsuchimochi ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Immune Cell ◽  
Vascular Protection ◽  
Small Peptide ◽  
Inflammatory Cytokine Production ◽  
Cell Recruitment ◽  
Acyl Ghrelin ◽  
Immune Cell Recruitment

Ghrelin is a small peptide with important roles in the regulation of appetite, gut motility, glucose homeostasis as well as cardiovascular protection. This review highlights the role that acyl ghrelin plays in maintaining normal endothelial function by maintaining the balance of vasodilator-vasoconstrictor factors, inhibiting inflammatory cytokine production and immune cell recruitment to sites of vascular injury and by promoting angiogenesis.

scholarly journals NFAM1 Promotes Pro-Inflammatory Cytokine Production in Mouse and Human Monocytes

2022 ◽  
Vol 12 ◽  
Author(s):  
Kathryn W. Juchem ◽  
Anshu P. Gounder ◽  
Jian Ping Gao ◽  
Elise Seccareccia ◽  
Narayana Yeddula ◽  
...  
Keyword(s):  
B Cell ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Immune Cell ◽  
Cellular Level ◽  
Human Monocytes ◽  
Inflammatory Cytokine Production ◽  
Tnf Α

NFAT activating protein with ITAM motif 1 (NFAM1) is an ITAM bearing-transmembrane receptor that has been reported to play a role in B cell signaling and development. We performed expression analysis of NFAM1 using publicly available gene expression data sets and found that NFAM1 expression is significantly induced in intestinal biopsies from Crohn’s disease (CD) and ulcerative colitis (UC) patients. At the cellular level, we further observed high expression of NFAM1 in monocytes and neutrophils, and low expression in B and T cells. To explore the role of NFAM1 in multiple immune cells and its potential role in IBD, we generated NFAM1-/- mice. In contrast with previous reports using NFAM1-transgenic mice, NFAM1-/- mice have no obvious defects in immune cell development, or B cell responses. Interestingly, NFAM1-/- monocytes produce reduced levels of TNF-α in response to activation by multiple IBD-relevant stimuli, including CD40L, TLR ligands and MDP. Additional cytokines and chemokines such as IL-6, IL-12, CCL3 and CCL4 are also reduced in CD40L stimulated NFAM1-/- monocytes. Collectively, these findings indicate that NFAM1 promotes monocyte activation, thereby amplifying the response to diverse stimuli. Similarly, we observed that deletion of NFAM1 in human monocytes reduces expression of CD40L-induced CCL4. Lastly, to assess the role of NFAM1 in IBD, we compared development of anti-CD40 induced colitis in NFAM1+/+ and NFAM1-/- mice. We found that although NFAM1 deletion had no impact on development of gut pathology, we did observe a decrease in serum TNF-α, confirming that NFAM1 promotes pro-inflammatory cytokine production in vivo. Taken together, we conclude that NFAM1 functions to amplify cytokine production and should be further evaluated as a therapeutic target for treatment of autoimmune disease.

scholarly journals Treatment of Intestinal Inflammation With Epicutaneous Immunotherapy Requires TGF-β and IL-10 but Not Foxp3+ Tregs

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Chen ◽  
M. Cecilia Berin ◽  
Virginia L. Gillespie ◽  
Hugh A. Sampson ◽  
David Dunkin
Keyword(s):  
Weight Loss ◽  
T Cells ◽  
Inflammatory Cytokine ◽  
T Regulatory Cells ◽  
Cytokine Production ◽  
Intestinal Inflammation ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
T Effector Cells ◽  
Epicutaneous Immunotherapy

Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET).Methods: RAG1−/− mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10−/−, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation.Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10−/− or CD4-dnTGFBRII mice.Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.

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