Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10–Deficient Mice

Matharu, Kabir; Mizoguchi, Emiko; Alonso-Cotoner, Carmen; Nguyen, Deanna D.; Mingle, Bethany; Iweala, Onyinye I.; McBee, Megan E.; Stefka, Andrew; Prioult, Guénolée; Haigis, Kevin M.; Bhan, Atul K.; Snapper, Scott B.; Murakami, Hidehiro; Schauer, David B.; Reinecker, Hans–Christian; Mizoguchi, Atsushi; Nagler, Cathryn R.

doi:10.1053/j.gastro.2009.07.004

Cited by 56 publications

(66 citation statements)

References 38 publications

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“…To explore whether the increased inflammatory phenotype observed after adoptive transfer of Il10 -/-Tlr4 -/-T cells was due to decreased Treg development, we checked the frequency of Foxp3 + cells by IHC in colonic tissue from Rag1 -/-recipients transferred with the indicated CD4 + T cell populations. Consistent with previous results (13), the presence of Foxp3 + cells was higher in the highly inflamed colons, i.e., the frequency of Foxp3 + Tregs arising from the Il10 -/-Tlr4 -/-CD45RB hi naive population was increased when compared with the number of Foxp3 + Tregs observed in the colons of mice receiving Il10 -/-CD45RB hi cells (Supplemental Figure 4, A and B). Similar numbers of Foxp3 + cells were found in the mice receiving Treg cells from B6 mice (cotransfer groups).…”

Section: Tlr4 Deficiency Aggravates Il-10-dependent Colitissupporting

confidence: 79%

“…A recent publication addressed the role of Treg function in the absence of IL-10 and TLR4 signals (i.e., Il10 -/-Tlr4 -/-mice) in a model of intestinal inflammation mediated by Helicobacter hepaticus (13). In accordance with our data, the authors reported an increase in intestinal inflammation in Il10 -/-Tlr4 -/-mice with enhanced production of Th1/Th17 cytokines from effector CD4 + T cells, accompanied by an increase in IFN-γ-producing Foxp3 + Treg cells.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

González‐Navajas

Fine²,

Law³

et al. 2010

J. Clin. Invest.

135

134

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Section: Tlr4 Deficiency Aggravates Il-10-dependent Colitissupporting

confidence: 79%

Section: Figurementioning

confidence: 99%

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

González‐Navajas

Fine²,

Law³

et al. 2010

J. Clin. Invest.

135

134

View full text Add to dashboard Cite

“…In contrast to an observation that rectal prolapse is frequently associated with the presence of chronic inflammatory bowel disease (5), POP has been found in animals with defective ECM proteins, including fibulin-3, fibulin-5, and lysyl oxidaselike-1 (LOXL-1) (an enzyme that predominantly catalyzes crosslinking of elastin) (6)(7)(8). Interestingly, these proteins are abundantly expressed in the vaginal wall and involved in synthesis and assembly of elastic fibers.…”

Section: Introductionmentioning

confidence: 86%

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans

Budatha¹,

Roshanravan²,

Zheng³

et al. 2011

J. Clin. Invest.

133

132

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Pelvic organ prolapse (POP) is a common condition affecting almost half of women over the age of 50. The molecular and cellular mechanisms underlying this condition, however, remain poorly understood. Here we have reported that fibulin-5, an integrin-binding matricellular protein that is essential for elastic fiber assembly, regulated the activity of MMP-9 to maintain integrity of the vaginal wall and prevented development of POP. In murine vaginal stromal cells, fibulin-5 inhibited the β 1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5 RGE/RGE ) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5 -/-), Fbln5 RGE/RGE mice were able to form intact elastic fibers and did not exhibit POP. However, treatment of mice with β-aminopropionitrile (BAPN), an inhibitor of matrix cross-linking enzymes, induced subclinical POP. Conversely, deletion of Mmp9 in Fbln5 -/-mice significantly attenuated POP by increasing elastic fiber density and improving collagen fibrils. Vaginal tissue samples from pre-and postmenopausal women with POP also displayed significantly increased levels of MMP-9. These results suggest that POP is an acquired disorder of extracellular matrix and that therapies targeting matrix proteases may be successful for preventing or ameliorating POP in women. IntroductionPelvic organ prolapse (POP) is characterized by abnormal protrusion of female pelvic organs involving the uterus, bladder, and vagina (reviewed in refs. 1-3). Epidemiologic studies indicate that (a) vaginal birth, aging, and increased body mass index are major risk factors for the development of POP and (b) more than 1 pathology may be involved to exhibit full anatomical loss of support. Although approximately 11% of women have surgery for POP or urinary incontinence in their lifetimes (4), to date, effective therapies to prevent progression of POP have not been established, thereby imposing profound social and financial burden to affected individuals (3).Despite a difference in anatomical position of pelvic organs relative to the body axis and pelvic floor, rodent models of POP have provided important tools to study underlying mechanisms of prolapse. In contrast to an observation that rectal prolapse is frequently associated with the presence of chronic inflammatory bowel disease (5), POP has been found in animals with defective ECM proteins, including fibulin-3, fibulin-5, and lysyl oxidaselike-1 (LOXL-1) (an enzyme that predominantly catalyzes crosslinking of elastin) (6-8). Interestingly, these proteins are abundantly expressed in the vaginal wall and involved in synthesis and assembly of elastic fibers. It is also known that uterosacral ligaments support the vaginal wall and that Hoxa11 is essential for formation of uterosacral ligaments in mice (9). Hoxa11-deficient mice exhibit increased mobility of the uterus; however,

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“…However, development of colitis itself was not blocked in MD-2/MDR1A dKO mice, implying that MD-2 signaling is required for the progression but not for the initiation of colitis in MDR1A deficiency. Notably, others have recently shown that LPS signaling via TLR4 protects against acute DSS colitis (63, 64) and chronic colitis in IL-10-null mice (65,66). Thus, LPS signaling can be either protective or destructive in the intestinal mucosa, depending on the genetic context.…”

Section: Discussionmentioning

confidence: 99%

Loss of TLR2 Worsens Spontaneous Colitis in MDR1A Deficiency through Commensally Induced Pyroptosis

Eyking

Klepak

et al. 2013

The Journal of Immunology

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Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b+ myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1β activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b+Ly6C+-derived IL-1β production and inflammation entirely depended on MyD88. TLR2/MDR1A double-knockout CD11b+ myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1β, consistent with pyroptosis. Inhibition of reactive oxygen species–mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis.

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Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10–Deficient Mice

Cited by 56 publications

References 38 publications

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans

Loss of TLR2 Worsens Spontaneous Colitis in MDR1A Deficiency through Commensally Induced Pyroptosis

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