Pathogenic and Protective Roles of MyD88 in Leukocytes and Epithelial Cells in Mouse Models of Inflammatory Bowel Disease

Asquith, Mark; Boulard, Olivier; Powrie, Fiona; Maloy, Kevin J.

doi:10.1053/j.gastro.2010.04.045

Cited by 93 publications

(95 citation statements)

References 41 publications

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“…Bone marrow transfer experiments showed that MyD88 signaling in hematopoietic cells mediated intestinal inflammation induced by H. hepaticus. Since both donor and acceptor mice in these experiments were RAG2-deficient, these results indicate that the proinflammatory effects of MyD88 in this colitis model reside in innate immune cells [44]. This is in accordance with the fact that colitis development in Il-10 -/-mice relies on MyD88 signaling and NF-κB activation in myeloid cells [22,23].…”

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actisupporting

confidence: 72%

“…These studies together suggest that the detrimental effects of NF-κB activation in the gut are, at least in part, mediated by MyD88-induced signaling in myeloid cells. In contrast, because irradiated Rag2 -/-/Myd88 +/+ mice reconstituted with Rag2 -/-/Myd88 -/-bone marrow cells did not display the spontaneous lethality observed in Rag2 -/-/ Myd88 -/-mice [44], the authors concluded that MyD88 signaling in epithelial cells is critical for host survival in the absence of adaptive immunity. Although reciprocal bone marrow transfer experiments could not be performed in this study, and although necessary experiments with IEC-specific MyD88 deficiency are missing, several indications support the hypothesis that MyD88 signaling in IECs indeed serves beneficial purposes in the gut immune system.…”

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 65%

“…A recent study attempted to distinguish the intestinal cell types responsible for the beneficial and detrimental effects of MyD88 signaling using Helicobacter hepaticus-induced colitis as a model [44]. Bone marrow transfer experiments showed that MyD88 signaling in hematopoietic cells mediated intestinal inflammation induced by H. hepaticus.…”

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 99%

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NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

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Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actisupporting

confidence: 72%

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 65%

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 99%

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NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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“…Using a model of Helicobacter hepaticus-induced chronic inflammation, a recent study showed MyD88 signaling in leukocytes to be responsible for the phenotype (30). Also, using IL-10-deficient mice as a model of chronic T cell-dependent colitis, depletion of IKKβ in the myeloid compartment prolongs survival.…”

Section: Discussionmentioning

confidence: 99%

MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

Brandl

Sun

Neppl

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

133

129

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Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N -ethyl- N -nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLR→MyD88→AREG/EREG→EGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.

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“…31 Epithelial signaling through the interleukin-1 and Toll-like receptor adapter molecule MyD88 as well as the MyD88 adaptor-like (Mal) was shown to promote epithelial integrity in models of enteric inflammation and infection. 2,[32][33][34][35] The phenotype of MyD88 ¡/¡ mice might at least in part be the result of a dysfunctional mucus layer since mucus production, antimicrobial peptide and RegIIIg expression, as well as luminal SIgA transport were all shown to require intact epithelial MyD88 signaling. 11,36 Accordingly, the thinner inner colonic mucus layer observed in germ-free mice was restored to the size of the one observed in conventional mice by administration of Toll-like receptor ligands.…”

mentioning

confidence: 99%