MyD88 signaling promotes both mucosal homeostatic and fibrotic responses during Salmonella-induced colitis

Månsson, Lisa; Montero, Marinieve; Zarepour, Maryam; Bergstrom, Kirk; Ma, Cun‐Gen; Huang, Tina; Man, C.; Grassl, Guntram A.

doi:10.1152/ajpgi.00038.2012

Cited by 21 publications

(22 citation statements)

References 41 publications

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“…These observations suggest that RORα does not influence initial inflammatory responses, or the host's ability to clear the infection, but rather plays a specific role in generating a pro-fibrotic response in the gut during late stages of chronic Salmonella infection. The apparent disconnect between bacterial colonization the severity of fibrosis is consistent with previous reports which demonstrate that intestinal fibrosis does not require the presence of Salmonella as a persistent inflammatory stimulus (31,32). Instead, the pathology becomes self-propagating and is largely irrespective of interventions that attempt to reduce pathogen burdens or repress early inflammatory responses.…”

Section: Discussionsupporting

confidence: 89%

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

Gold

Hughes

et al. 2016

Sci. Immunol.

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Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that Rora-deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition and reduced fibroblast accumulation. Although Rora is best known for its role in ILC2 development, we find that Salmonella-induced fibrosis is independent of eosinophils, STAT6 signaling and Th2 cytokine production arguing that this process is largely ILC2-independent. Instead, we observe reduced levels of ILC3-and T cellderived IL-17A and IL-22 in infected gut tissues. Furthermore, using Rora sg/sg /Rag1 −/− bone marrow chimeric mice, we show that restoring ILC function is sufficient to re-establish IL-17A and IL-22 production and a profibrotic phenotype. Our results show that RORα-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn's-like diseases.

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Section: Discussionsupporting

confidence: 89%

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

Gold

Hughes

et al. 2016

Sci. Immunol.

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“…also described a colonic gene profile associated with both inflammation and fibrosis. COX-2 is a marker which for decades has clearly been associated with acute inflammation [25], [26], [27], [28] but which also increases significantly with time in fibrosis models, pulmonary fibrosis [29] and colonic fibrosis included [30]. In our observation a similar relationship between COX-2 and MR parameters linked both fibrosis and inflammation.…”

Section: Discussionsupporting

confidence: 73%

Magnetic Resonance Colonography for Fibrosis Assessment in Rats with Chronic Colitis

et al. 2014

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BackgroundMagnetic resonance colonography (MRC) has been developed to assess inflammatory bowel diseases. We aimed to assess the feasibility of MRC in rats with TNBS-induced chronic colitis and to confront imaging results with fibrosis and stenosing features of the model.Materials and MethodsChronic colitis was induced in 12 rats by weekly intra-rectal injection of increasing doses of TNBS for 6 weeks, while 8 control rats received the vehicle. At week 7, MRC was performed. Fibrosis scores were assessed and fibrosis mediators measured.ResultsChronic colitis was associated with significant body weight loss (p<0.0001) and higher colon weight/length compared to controls (p = 0.0004). Fibrosis mediators and histological scores were significantly higher in rats with TNBS than in controls: α-SMA expression (0.9 versus 0.61, p = 0.0311) and fibrosis score (p = 0.0308). Colon wall thickness was higher in rats with TNBS than in controls: maximal thickness (2.38 versus 0.74 mm, p<0.0001) and minimal thickness (1.33 versus 0.48 mm, p<0.0001). Wall signal intensity on T2w images was higher in rats with TNBS than in controls (9040 versus 6192, p = 0.0101) and correlated with fibrosis score (r = 0.5214; p = 0.04). Luminal narrowing was higher in rats with TNBS (50.08 versus 10.33%, p<0.0001) and correlated with α-SMA expression (r = 0.5618; p = 0.01). Stenosis was observed in 7/9 rats with TNBS and in no controls (p = 0.0053).ConclusionsMRC is feasible and easily distinguishes rats with colitis from controls. MRC signs correlated with fibrosis parameters. MRC evaluation may be part of a new anti-fibrosis drug assessment in experimental models of chronic colitis.

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“…The two most commonly used mouse strains are C57/BL6 and BALB/c, but since these strains suffer from a loss-of-function mutation in their nramp1 genes, they are extremely susceptible to Salmonella infec- tion (6). Recently we have shown the applicability of the attenuated ⌬aroA strain of S. Typhimurium for studying colitis in these mouse strains (7). Our present studies found that Muc2 plays a critical role in host defense against S. Typhimurium.…”

Section: Discussionmentioning

confidence: 48%

“…It was surprising that Muc2 Ϫ/Ϫ mice succumbed to ⌬aroA S. Typhimurium, considering that infection by this pathogen is not normally lethal, even to severely immunodeficient mice (7,33). Considering that their symptoms (hunched appearance, piloerection, and reduced activity) observed during Salmonella infection are typically signs of a systemic disease (34), we decided to compare inflammatory responses within the livers of WT and Muc2 Ϫ/Ϫ mice.…”

Section: Muc2mentioning

confidence: 99%

“…However, the two mouse strains most commonly used for the Salmonella enterocolitis model (C57/BL6 and BALB/c) are known to possess a mutation in their nramp1 genes, leaving these mice highly susceptible to S. Typhimurium and succumbing rapidly to infection (6). To circumvent this limitation, we have recently described a model using the attenuated S. Typhimurium ⌬aroA mutant strain, which still causes severe colitis but typically causes no mortality, even in highly susceptible mouse strains (7). Most studies employing the enterocolitis model have focused on dissecting the virulence strategies of S. Typhimurium or exploring the specific host factors that drive the resulting inflammation.…”

mentioning

confidence: 99%

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The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

et al. 2013

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c Salmonella enterica serovar Typhimurium is a model organism used to explore the virulence strategies underlying Salmonella pathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection against Salmonella is still unclear. The intestinal mucus layer is composed primarily of the Muc2 mucin, a heavily O-glycosylated glycoprotein. The core 3-derived O-glycans of Muc2 are synthesized by core 3 ␤1,3-N-acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce Muc2 but display a thinner intestinal mucus barrier. We began our investigations by comparing Salmonella-induced colitis and mucus dynamics in Muc2-deficient (Muc2 ؊/؊ ) mice, C3GnT ؊/؊ mice, and wild-type C57BL/6 (WT) mice. Salmonella infection led to increases in luminal Muc2 secretion in WT and C3GnT ؊/؊ mice. When Muc2 ؊/؊ mice were infected with Salmonella, they showed dramatic susceptibility to infection, carrying significantly higher cecal and liver pathogen burdens, and developing significantly higher barrier disruption and higher mortality rates, than WT mice. We found that the exaggerated barrier disruption in infected Muc2 ؊/؊ mice was invA dependent. We also tested the susceptibility of C3GnT ؊/؊ mice and found that they carried pathogen burdens similar to those of WT mice but developed exaggerated barrier disruption. Moreover, we found that Muc2 ؊/؊ mice were impaired in intestinal alkaline phosphatase (IAP) expression and lipopolysaccharide (LPS) detoxification activity in their ceca, potentially explaining their high mortality rates during infection. Our data suggest that the intestinal mucus layer (Muc2) and core 3 O-glycosylation play critical roles in controlling Salmonella intestinal burdens and intestinal epithelial barrier function, respectively.

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MyD88 signaling promotes both mucosal homeostatic and fibrotic responses during Salmonella-induced colitis

Abstract: GA, Vallance BA. MyD88 signaling promotes both mucosal homeostatic and fibrotic responses during Salmonella-induced colitis.

Cited by 21 publications

References 41 publications

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

Magnetic Resonance Colonography for Fibrosis Assessment in Rats with Chronic Colitis

The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

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