scholarly journals A235 THE INFLUENCE OF IL10 ON COLITIS DEVELOPMENT IN NOD2 DEFICIENT MICE

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 112-112
Author(s):  
M D Gryfe ◽  
K Croitoru ◽  
A Goethel ◽  
A Luchak
Keyword(s):  
Intestinal Inflammation ◽  
Neutrophil Infiltration ◽  
Interleukin 10 ◽  
Lipocalin 2 ◽  
Double Knockout ◽  
Intestinal Homeostasis ◽  
Funding Agencies ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
Deficient Mice

Abstract Background Inflammatory bowel disease (IBD) risk genes include interleukin-10 (IL10) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Although their specific roles in intestinal inflammation are unclear, these proteins are involved in modulating host-microbe interactions and intestinal homeostasis. Aims Since IL10 is an anti-inflammatory cytokine that maintains intestinal homeostasis, we hypothesized that mice deficient for both IL10 and NOD2 would be more susceptible to colitis than mice with only the NOD2 deletion. Methods In-house generated NOD2-/- x IL10-/- (double knockout) and NOD2-/- x IL10+/+ littermate mice of varying ages (3–20 weeks of age) were weighed and stools samples were collected at weekly intervals. Lipocalin-2 (LCN-2) levels were quantified in stool by ELISA. A subset of mice from each genotype received 3.5% dextran sulfate sodium (DSS) supplemented water for 5 days starting at eight weeks of age. Mice were sacrificed after two days of regular water, on day 8. Results Untreated NOD2-/- x IL10+/+ mice showed higher fecal LCN-2 compared to NOD2-/- x IL10-/- mice at all ages, although this trend was not significant. Within DSS-treated mice, LCN-2 levels in stool collected at sacrifice (on day 8) were significantly higher in NOD2-/- x IL10+/+ mice, compared to NOD2-/- x IL10-/- mice. Moreover, only 50% (2 of 4) of the NOD2-/- x IL10+/+ DSS-treated mice survived to day 8, whereas all four NOD2-/- x IL10-/- DSS-treated mice survived. Conclusions Fecal LCN-2 indicates the extent of neutrophil infiltration, which is reflective of the severity of intestinal inflammation. As such, LCN-2 levels suggest that NOD2-/- x IL10+/+ mice have higher baseline inflammation and are more susceptible to DSS-induced colitis than double knockout NOD2-/- x IL10-/- mice. These results are contrary to our hypothesis that combining IL10 and NOD2 deficiency would increase colitis susceptibility as compared to NOD2 deficiency alone. This suggests that the absence of IL10 may actually reduce the severity of DSS-induced colitis in NOD2 deficient mice. The role of IL10 in modulating the gut microbiome using this model remains to be assessed. Funding Agencies CAG

scholarly journals Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Naresh S Redhu ◽  
Vasudevan Bakthavatchalu ◽  
Evan A Conaway ◽  
Dror S Shouval ◽  
Amy Tsou ◽  
...  
Keyword(s):  
Infant Development ◽  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Postnatal Period ◽  
Macrophage Function ◽  
Murine Colitis ◽  
Macrophage Depletion ◽  
Macrophage Dysfunction ◽  
Inflammatory Bowel ◽  
Deficient Mice

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.

scholarly journals Studies on the Interleukin-10 Gene in Animal Models of Colitis

2001 ◽  
Vol 15 (8) ◽  
pp. 557-558
Author(s):  
Hugh J Freeman
Keyword(s):  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Inflammatory Bowel ◽  
Deficient Mice

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.

scholarly journals Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

2014 ◽  
Vol 82 (5) ◽  
pp. 1949-1958 ◽  
Author(s):  
Sara M. Dann ◽  
Christine Le ◽  
Barun K. Choudhury ◽  
Houpu Liu ◽  
Omar Saldarriaga ◽  
...  
Keyword(s):  
Immune Responses ◽  
Intestinal Inflammation ◽  
Acute Infection ◽  
Interleukin 10 ◽  
Mucosal Inflammation ◽  
Immune Functions ◽  
Citrobacter Rodentium ◽  
Microbial Infection ◽  
Content Type ◽  
Deficient Mice

ABSTRACTInterleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogenCitrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transientC. rodentiuminfection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppressin vitroTh17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolvingC. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.

scholarly journals Gut mélange à trois: fluctuating selection modulated by microbiota, host immune system, and antibiotics

2021 ◽  
Author(s):  
Hugo Condessa Barreto ◽  
Beatriz Abreu ◽  
Isabel Gordo
Keyword(s):  
Immune System ◽  
Iron Homeostasis ◽  
Host Immune System ◽  
Iron Availability ◽  
Lipocalin 2 ◽  
Fluctuating Selection ◽  
Microbe Interactions ◽  
Host Microbe Interactions

Iron is critical in host-microbe interactions, and its availability is under tight regulation in the mammalian gut. Antibiotics and inflammation are known to perturb iron availability in the gut, which could subsequently alter host-microbe interactions. Here, we show that an adaptive allele of iscR, encoding a major regulator of iron homeostasis of Escherichia coli, is under fluctuating selection in the mouse gut. In vivo competitions in immune-competent, immune-compromised, and germ-free mice reveal that the selective pressure on an iscR mutant E. coli is modulated by the presence of antibiotics, other members of the microbiota, and the immune system. In vitro assays show that iron availability is an important mediator of the iscR allele fitness benefits or costs. We identify Lipocalin-2, a host's innate immune system protein that prevents bacterial iron acquisition, as a major host mechanism underlying fluctuating selection of the iscR allele. Our results provide a remarkable example of strong fluctuating selection acting on bacterial iron regulation in the mammalian gut.

scholarly journals Helicobacter hepaticus-Induced Colitis in Interleukin-10-Deficient Mice: Cytokine Requirements for the Induction and Maintenance of Intestinal Inflammation

2001 ◽  
Vol 69 (7) ◽  
pp. 4232-4241 ◽  
Author(s):  
Marika C. Kullberg ◽  
Antonio Gigliotti Rothfuchs ◽  
Dragana Jankovic ◽  
Patricia Caspar ◽  
Thomas A. Wynn ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Inos Mrna ◽  
Th1 Cells ◽  
Mrna Levels ◽  
Helicobacter Hepaticus ◽  
Tnf Α ◽  
Disease Induction ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT We have previously shown that specific-pathogen-free interleukin-10 (IL-10)-deficient (IL-10 KO) mice reconstituted withHelicobacter hepaticus develop severe colitis associated with a Th1-type cytokine response. In the present study, we formally demonstrate that IL-12 is crucial for disease induction, because mice deficient for both IL-10 and IL-12 p40 show no intestinal pathology following H. hepaticus infection. By using monoclonal antibodies (MAbs) to IL-12, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), we have further analyzed the role of these cytokines in the maintenance of the Th1 response and inflammation in IL-10 KO mice with established H. hepaticus-induced colitis. Treatment of infected colitic IL-10 KO mice with anti-IL-12 p40 resulted in markedly reduced intestinal inflammation, colonic IFN-γ, TNF-α, and inducible nitric oxide synthase (iNOS) mRNA levels, and H. hepaticus-specific IFN-γ secretion by mesenteric lymph node (MLN) cells compared to the findings in control MAb-treated mice. Moreover, the diminished pathology was associated with decreased numbers of colonic CD3+ T cells and significantly reduced frequencies ofHelicobacter-reactive CD4+ Th1 cells in MLN. In contrast, anti-IFN-γ and/or anti-TNF-α had no effect on intestinal inflammation in IL-10 KO mice with established colitis. Using IL-10/IFN-γ double-deficient mice, we further show that IFN-γ is not required for the development of colitis follwing H. hepaticus infection. MLN cells from infected IL-10/IFN-γ KO animals secreted elevated amounts of IL-12 and TNF-α following bacterial antigen stimulation, indicating alternative pathways of disease induction. Taken together, our results demonstrate a crucial role for IL-12 in both inducing and sustaining intestinal inflammation through recruitment and maintenance of a pool of pathogenic Th1 cells.

scholarly journals Excess neutrophil infiltration during cytomegalovirus brain infection of interleukin-10-deficient mice

2010 ◽  
Vol 227 (1-2) ◽  
pp. 101-110 ◽  
Author(s):  
Manohar B. Mutnal ◽  
Maxim C.-J. Cheeran ◽  
Shuxian Hu ◽  
Morgan R. Little ◽  
James R. Lokensgard
Keyword(s):  
Neutrophil Infiltration ◽  
Interleukin 10 ◽  
Brain Infection ◽  
Deficient Mice

scholarly journals Altered enteric microbiota ecology in interleukin 10-deficient mice during development and progression of intestinal inflammation

Gut Microbes ◽  
2013 ◽  
Vol 4 (4) ◽  
pp. 316-324 ◽  
Author(s):  
Nitsan Maharshak ◽  
Christopher D. Packey ◽  
Melissa Ellermann ◽  
Sayeed Manick ◽  
Jennica P. Siddle ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Deficient Mice

scholarly journals The Role of Gut Microbiota Biomodulators on Mucosal Immunity and Intestinal Inflammation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1234 ◽  
Author(s):  
Chiara Amoroso ◽  
Federica Perillo ◽  
Francesco Strati ◽  
Massimo Fantini ◽  
Flavio Caprioli ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Immune Responses ◽  
Targeted Therapies ◽  
Intestinal Inflammation ◽  
Cost Effective ◽  
Bowel Diseases ◽  
Current Therapies ◽  
Microbe Interactions ◽  
Inflammatory Bowel ◽  
Host Microbe Interactions

Alterations of the gut microbiota may cause dysregulated mucosal immune responses leading to the onset of inflammatory bowel diseases (IBD) in genetically susceptible hosts. Restoring immune homeostasis through the normalization of the gut microbiota is now considered a valuable therapeutic approach to treat IBD patients. The customization of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation, is therefore considered to support current therapies in IBD management. In this review, we will discuss recent advancements in the understanding of host−microbe interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. By considering gut microbiota dysbiosis as a key feature for the establishment of chronic inflammatory events, in the near future it will be suitable to design new cost-effective, physiologic, and patient-oriented therapeutic strategies for the treatment of IBD that can be applied in a personalized manner.

scholarly journals The Multifaceted Role of Commensal Microbiota in Homeostasis and Gastrointestinal Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Marcelo José Barbosa Silva ◽  
Matheus Batista Heitor Carneiro ◽  
Brunna dos Anjos Pultz ◽  
Danielle Pereira Silva ◽  
Mateus Eustáquio de Moura Lopes ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Gastrointestinal Diseases ◽  
Commensal Microbiota ◽  
Microbe Interactions ◽  
Mucosal Homeostasis ◽  
Diverse Community ◽  
Pathogenic Microbes ◽  
Host Microbe Interactions

The gastrointestinal tract houses a complex and diverse community of microbes. In recent years, an increased understanding of the importance of intestinal microbiota for human physiology has been gained. In the steady state, commensal microorganisms have a symbiotic relationship with the host and possess critical and distinct functions, including directly influencing immunity. This means that recognition of commensal antigens is necessary for the development of complete immune responses. Therefore, the immune system must face the challenge of maintaining mucosal homeostasis while dealing with undue passage of commensal or pathogenic microbes, as well as the host nutritional status or drug use. Disruption of this fine balance has been associated with the development of several intestinal inflammatory diseases. In this review, we discuss the mechanisms involved in the modulation of host-microbe interactions and how the breakdown of this homeostatic association can lead to intestinal inflammation and pathology.

Sign in / Sign up

Export Citation Format

Share Document