P158 LOSS OF AUTOTAXIN ALTERS INNATE AND ADAPTIVE IMMUNE MECHANISM AND PROMOTES SPONTANEOUS COLITIS IN IL10-KO MICE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S33-S33
Author(s):  
Su Jin Kim ◽  
Cody Howe ◽  
Jonathon Mitchell ◽  
Eunok Im ◽  
Sang Rhee
Keyword(s):  
T Cells ◽  
Complex Formation ◽  
Lipid Rafts ◽  
Lamina Propria ◽  
Intestinal Mucosa ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Bacterial Load ◽  
Serum Samples ◽  
Adaptive Immune

Abstract Background & Aims Autotaxin (Atx) is a secreted enzyme converting lysophosphatidylcholine (LPC) and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Given the high affinity of LPC to cholesterol and the enrichment of cholesterol and sphingolipids in lipid rafts wherein LPS sensor Toll-like receptor 4 (TLR4) and its co-receptor CD14 reside, we hypothesized that Atx deficiency inhibits TLR4-mediated innate and adaptive immunity; thereby, accelerating the susceptibility to microbe-induced intestinal inflammation. Method We generated myeloid cell lineage-restricted Atx-knockout (ko) mice (AtxdME/dME) to study TLR4-mediated immune and inflammatory responses and investigated LPS-receptor complex formation through fluorescence resonance energy transfer technique, confocal microscopy, and flow cytometry. Lamina propria CD4+ T cells and bacterial load in the intestinal mucosa were examined. An impact of Atx deficiency in inflammatory bowel diseases (IBD) was investigated using AtxdME/dME;Il10-/- mice that have both Atx-deletion in myeloid cells and a global Il10 deletion. We examined the serum samples from IBD patients. Results With peritoneal macrophages from AtxdME/dME mice, we identified that Atx-ko disrupted the integrity of lipid rafts at the plasma membrane, resulting in the inhibition of TLR4 complex formation. Accordingly, the recruitment of adaptor molecules to TLR4 was suppressed, and TLR4-mediated responses were substantially reduced in Atx-ko macrophages. TLR4-induced innate immunity such as phagocytosis was attenuated in Atx-ko macrophages. The activation of CD4+ effector T cells and regulatory T cells was diminished in the lamina propria lymphocytes of AtxdME/dME mice compared to that of Atx+/+ littermates. Consequently, AtxdME/dME mice had a higher bacterial prevalence in the intestinal mucosa compared to controls. Just like the notion that commensal microbes translocated from the lumen into the intestinal mucosa can elicit spontaneous colitis in Il10-/- mice, combining AtxdME/dME with Il10-/- mice (AtxdME/dME; Il10-/-) did accelerate spontaneous colitis development. AtxdME/dME; Il10-/- mice had gross inflammation occurring throughout the colon, massive neutrophil infiltration and necrosis in the colonic mucosa, and increased mortality (Log-rank P=0.0046), while Atx+/+;Il10-/- littermates are normal. Notably, ATX serum protein level was lower in UC (n=26) and CD (n=34) patients compared to the level in normal subjects (n=26) (P<0.001), indicating an association of reduced ATX levels with the intestinal inflammation. Conclusions Collectively, we found that Atx deficiency suppresses TLR4-mediated innate and adaptive immune mechanisms; thereby accelerating the susceptibility to microbe-induced gut inflammation.

scholarly journals Egr2 and 3 control inflammation, but maintain homeostasis, of PD-1high memory phenotype CD4 T cells

2020 ◽  
Vol 3 (9) ◽  
pp. e202000766
Author(s):  
Alistair LJ Symonds ◽  
Wei Zheng ◽  
Tizong Miao ◽  
Haiyu Wang ◽  
TieShang Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Active Rheumatoid Arthritis ◽  
Inflammatory Responses ◽  
Homeostatic Proliferation ◽  
Adaptive Responses ◽  
Memory Phenotype ◽  
Adaptive Immune ◽  
Cd4 Cell

The transcription factors Egr2 and 3 are essential for controlling inflammatory autoimmune responses of memory phenotype (MP) CD4 T cells. However, the mechanism is still unclear. We have now found that the Egr2+ subset (PD-1high MP) of MP CD4 T cells expresses high levels of checkpoint molecules (PD-1 and Lag3) and also markers of effector T cells (CXCR3 and ICAM-1). Egr2/3 are not required for PD-1high MP CD4 cell development but mediate a unique transcriptional programme that effectively controls their inflammatory responses, while promoting homeostatic proliferation and adaptive responses. Egr2 negative PD-1high MP CD4 T cells are impaired in homeostatic proliferation and adaptive responses against viral infection but display inflammatory responses to innate stimulation such as IL-12. PD-1high MP CD4 T cells have recently been implicated in rheumatoid arthritis pathogenesis, and we have now found that Egr2 expression is reduced in PD-1high MP CD4 T cells from patients with active rheumatoid arthritis compared with healthy controls. These findings demonstrate that Egr2/3 control the inflammatory responses of PD-1high MP CD4 T cells and maintain their adaptive immune fitness.

scholarly journals Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells

2019 ◽  
Vol 2 (1) ◽  
pp. e201800229 ◽  
Author(s):  
Claudia Burrello ◽  
Gabriella Pellegrino ◽  
Maria Rita Giuffrè ◽  
Giulia Lovati ◽  
Ilaria Magagna ◽  
...  
Keyword(s):  
Lamina Propria ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Lymphoid Tissues ◽  
Inkt Cells ◽  
Inflammatory Processes ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) pathogenesis has been linked to the aberrant activation of the Gut-associated lymphoid tissues against components of the intestinal microbiota. Although the contribution of CD4+ T helper cells to inflammatory processes is being increasingly acknowledged, the functional engagement of human invariant natural killer T (iNKT) cells is still poorly defined. Here, we evaluated the functional characteristics of intestinal iNKT cells during IBD pathogenesis and to exploit the role of mucosa-associated microbiota recognition in triggering iNKT cells’ pro-inflammatory responses in vivo. Lamina propria iNKT cells, isolated from surgical specimens of active ulcerative colitis and Crohn’s disease patients and non-IBD donors, were phenotypically and functionally analyzed ex vivo, and stable cell lines and clones were generated for in vitro functional assays. iNKT cells expressing a pro-inflammatory cytokine profile were enriched in the lamina propria of IBD patients, and their exposure to the mucosa-associated microbiota drives pro-inflammatory activation, inducing direct pathogenic activities against the epithelial barrier integrity. These observations suggest that iNKT cell pro-inflammatory functions may contribute to the fuelling of intestinal inflammation in IBD patients.

scholarly journals Interleukin (IL)-23 mediates Toxoplasma gondii–induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

2009 ◽  
Vol 206 (13) ◽  
pp. 3047-3059 ◽  
Author(s):  
Melba Muñoz ◽  
Markus M. Heimesaat ◽  
Kerstin Danker ◽  
Daniela Struck ◽  
Uwe Lohmann ◽  
...  
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Lamina Propria ◽  
Th17 Cells ◽  
Intestinal Inflammation ◽  
Gelatinase A ◽  
Intestinal Lamina Propria ◽  
Small Intestinal ◽  
Th1 Cytokines

Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.

scholarly journals Interleukin-23 drives innate and T cell–mediated intestinal inflammation

2006 ◽  
Vol 203 (11) ◽  
pp. 2473-2483 ◽  
Author(s):  
Sophie Hue ◽  
Philip Ahern ◽  
Sofia Buonocore ◽  
Marika C. Kullberg ◽  
Daniel J. Cua ◽  
...  
Keyword(s):  
T Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Inflammatory Disorder ◽  
Chronic Inflammatory Disorder ◽  
Adaptive Immune ◽  
Proinflammatory Responses ◽  
Interleukin 23 ◽  
Immune Pathology ◽  
Chronic Intestinal Inflammation

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract involving aberrant activation of innate and adaptive immune responses. We have used two complementary models of IBD to examine the roles of interleukin (IL)-12 family cytokines in bacterially induced intestinal inflammation. Our results clearly show that IL-23, but not IL-12, is essential for the induction of chronic intestinal inflammation mediated by innate or adaptive immune mechanisms. Depletion of IL-23 was associated with decreased proinflammatory responses in the intestine but had little impact on systemic T cell inflammatory responses. These results newly identify IL-23 as a driver of innate immune pathology in the intestine and suggest that selective targeting of IL-23 represents an attractive therapeutic approach in human IBD.

MIP-3α neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice

2007 ◽  
Vol 292 (5) ◽  
pp. G1263-G1271 ◽  
Author(s):  
Kianoosh Katchar ◽  
Ciarán P. Kelly ◽  
Sarah Keates ◽  
Michael J. O'Brien ◽  
Andrew C. Keates
Keyword(s):  
Inflammatory Bowel Disease ◽  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
Lamina Propria ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Colonic Injury ◽  
Neutralizing Monoclonal Antibody ◽  
Inflammatory Bowel

A characteristic feature of human inflammatory bowel disease, particularly Crohn's disease, is the presence of activated CD4+T cells. Recently, we have shown that colonic epithelial cell production of macrophage inflammatory protein (MIP)-3α, a CD4 T cell-directed chemokine, is elevated in inflammatory bowel disease. However, the functional relevance of MIP-3α production during intestinal inflammation is poorly understood. The aim of this study was to determine whether MIP-3α production is increased during murine 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and to examine the effect of anti-MIP-3α neutralizing monoclonal antibody administration in this model. We found that the administration of TNBS significantly increased colonic MIP-3α protein levels in Balb/c mice. Consistent with this, a marked increase in the number of CCR6-bearing lamina propria CD4+and CD8+T cells was also observed in TNBS-treated animals. Treatment of mice with an anti-MIP-3α neutralizing monoclonal antibody significantly reduced TNBS-mediated increases in colonic weight-to-length ratio, mucosal ulceration, histological damage, and myeloperoxidase activity. TNBS-mediated increases in the number of CCR6-bearing lamina propria T cells were also substantially reduced by anti-MIP-3α neutralizing monoclonal antibody treatment. Taken together, our findings indicate that blockade of MIP-3α bioactivity can significantly reduce TNBS-mediated colonic injury and T cell recruitment, suggesting a role for this chemokine in the pathophysiology of intestinal inflammation.

scholarly journals Microbial Amyloids Induce Interleukin 17A (IL-17A) and IL-22 Responses via Toll-Like Receptor 2 Activation in the Intestinal Mucosa

2012 ◽  
Vol 80 (12) ◽  
pp. 4398-4408 ◽  
Author(s):  
Jessalyn H. Nishimori ◽  
Tiffanny N. Newman ◽  
Gertrude O. Oppong ◽  
Glenn J. Rapsinski ◽  
Jui-Hung Yen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Intestinal Mucosa ◽  
Amyloid Fibrils ◽  
Inflammatory Responses ◽  
Toll Like Receptor ◽  
T Helper ◽  
Content Type ◽  
Interleukin 17A ◽  
Toll Like Receptor 2

ABSTRACTThe Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phylaFirmicutes,Bacteroidetes, andProteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogenSalmonella entericaserotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. AcsgBAmutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to theS. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted duringS. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent mannerin vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations—CD4+T helper cells, cytotoxic CD8+T cells, and γδ T cells—produced IL-17A in response to curli fibrils in the intestinal mucosa duringS. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.

scholarly journals P010 GSDMB-mediated pyroptosis exacerbates intestinal inflammation by destroying intestinal epithelium in Crohn’s disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S129-S131
Author(s):  
W Gong ◽  
P Liu ◽  
J Ren
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
Epithelial Cells ◽  
Intestinal Mucosa ◽  
Cd8 T Cells ◽  
Intestinal Inflammation ◽  
Disease Risk ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Epithelial Injury

Abstract Background Intestinal epithelial injury acts an essential role in the pathogenesis and development of Crohn’s disease (CD). Recent studies indicated that gasdermin D (GSDMD) mediated pyroptosis in intestinal epithelial cell (IEC) contributes to the epithelial injury during intestinal inflammation. However, how gasdermin B (GSDMB) mediated pyroptosis regulates intestinal epithelial injury in CD remains unknown. Methods We studied the characteristics of GSDMB mediated pyroptosis in CD patients and intestinal epithelial cells (Caco-2, HT-29 and primary IECs). The CD8+ T cells were extracted from intestinal mucosa of CD patients and health controls, and then co cultured with normal primary IECs to observe the pyroptosis of IECs. We further analyzed the CD8+ T cell subsets that promote pyroptosis in intestinal biopsies of CD patients. In addition, we screened out four single nucleotide polymorphism (SNP) of GSDMB that related to disease risk of CD in the public IBD exomes database (https://ibd.broadinstitute.org/), and investigated their effects on pyroptosis. Results GSDMB mediated pyroptosis was notably increased in intestinal mucosa of active human CD, and only existed in intestinal epithelial cells (Figure 1). Granzyme A (GrzA) initiated the killing results by the cleavage of GSDMB in intestinal epithelial cells, and interferon gamma (IFN-γ) up-regulated GSDMB expression in intestinal epithelial cells and promoted pyroptosis (Figure 2). GSDMB in primary IECs was significantly cleaved when co cultured with CD8+ T cells from active CD patients, while the phenomenon weakened a lot when GrzA in CD8+ T cells or GSDMB in epithelial cells was knocked down (Figure 3). We also found that IL26 possive CD8+ T cells were the main CD8+ T cells subsets secreting GrzA (Figure 3). We screened out two SNP of GSDMB related to increased disease risk of CD (rs2305480 and rs11078928) and two related to decreased disease risk (rs35104165 and rs143933205), and constructed these four mutant plasmids. Compared with wild type of GSDMB, rs2305480 promoted the cleavage while rs35104165 blocked the cleavage (Figure 4). Conclusion GSDMB-mediated pyroptosis results in intestinal epithelial injury, which will exacerbate intestinal inflammation. Modulation of the GSDMB-mediated pyroptosis emerges as a potential therapeutic strategy to target epithelium damage and treat CD.

scholarly journals IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells

2012 ◽  
Vol 209 (9) ◽  
pp. 1595-1609 ◽  
Author(s):  
Margherita Coccia ◽  
Oliver J. Harrison ◽  
Chris Schiering ◽  
Mark J. Asquith ◽  
Burkhard Becher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Pathology ◽  
Bowel Diseases ◽  
Chronic Intestinal Inflammation

Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus–triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell–specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4+ T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4+ T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.

scholarly journals Synergy between intraepithelial lymphocytes and lamina propria T cells drives intestinal inflammation during infection

2011 ◽  
Vol 4 (6) ◽  
pp. 658-670 ◽  
Author(s):  
C E Egan ◽  
K J Maurer ◽  
S B Cohen ◽  
M Mack ◽  
K W Simpson ◽  
...  
Keyword(s):  
T Cells ◽  
Lamina Propria ◽  
Intestinal Inflammation ◽  
Intraepithelial Lymphocytes

scholarly journals Regulation of Murine Dendritic Cell Immune Responses by Helicobacter felis Antigen

2006 ◽  
Vol 74 (8) ◽  
pp. 4624-4633 ◽  
Author(s):  
Maureen L. Drakes ◽  
Steven J. Czinn ◽  
Thomas G. Blanchard
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Lamina Propria ◽  
Adaptive Immune Responses ◽  
Helicobacter Felis ◽  
Adaptive Immune ◽  
Pulsed Dc ◽  
Antigen Presenting

ABSTRACT Helicobacter infections are present in approximately 50% of humans, causing severe illnesses such as gastritis and malignancies. Dendritic cells (DC) are critical antigen-presenting cells which link innate and adaptive immune responses. The mechanism of dendritic cell regulation in Helicobacter-induced gastritis is poorly understood. These studies characterized DC isolated from the lamina propria of Helicobacter-infected mice and analyzed innate and adaptive immune responses elicited by Helicobacter antigen (Ag)-pulsed DC. The presence of DC was elevated in the gastric lamina propria infiltrate of infected mice in comparison with controls. After treatment with Helicobacter felis Ag, DC were polarized to secrete interleukin-6 as the dominant cytokine. In the presence of DC and Helicobacter Ag, responder allogeneic T cells in culture exhibited limited cell division. We suggest that the response of DC and T cells to Helicobacter Ag is critical to the chronic persistence of Helicobacter-induced gastritis.

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