Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury

Brown, Sarah; Riehl, Terrence E.; Walker, Monica R.; Geske, Michael J.; Doherty, Jason M.; Stenson, William F.; Stappenbeck, Thaddeus S.

doi:10.1172/jci29159

Cited by 238 publications

(220 citation statements)

References 44 publications

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“…Thus, efficient wound healing appears to be Myd88-independent for acute colonic mucosal injuries. One possible explanation for the difference of the two systems is that DSS inhibits epithelial proliferation that requires both TLR and prostaglandins to rescue it in WT mice (15). This finding is similar to skin, where Myd88 signaling was required for proper wound healing only when punch biopsies were inoculated with pathogenic microbes (20).…”

Section: Efficient Wound Healing Did Not Require Neutrophils or Tlr-smentioning

confidence: 90%

“…Recent studies have suggested that colonic epithelial stem cells are strongly influenced by their local stromal microenvironment and Myd88-dependent Toll-like receptor signaling during mucosal injury (7,15). We quantified the major stromal cell types in both the wound bed and adjacent crypt areas of WT and Myd88 Ϫ/Ϫ mice.…”

Section: Efficient Wound Healing Did Not Require Neutrophils or Tlr-smentioning

confidence: 99%

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Efficient colonic mucosal wound repair requires Trem2 signaling

Seno

Miyoshi²,

Brown³

et al. 2009

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

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The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkü hn. Stem cells lost because of damage or disease can be replaced by adjacent crypts that undergo fission. The close proximity of an extraordinary number of luminal microbes creates a challenge for this repair process; infection must be prevented while immune system activation and epithelial stem cell genetic damage must be minimized. To understand the factors that modulate crypt/stem cell replacement in the mouse colon, we developed an in vivo acute injury system analogous to punch biopsy of the skin. In contrast to epidermal stem cells, colonic epithelial progenitors did not migrate over the wound bed. Instead, their proliferative expansion was confined to crypts adjacent to wound beds and was delayed to the latter phase of healing. This increased epithelial proliferation was coincident with the infiltration of Trem2 expressing macrophages and increased expression of IL-4 and IL-13 in the wound bed. Interestingly, Trem2 ؊/؊ mice displayed slow and incomplete wound healing of colonic mucosal injuries. We found the latter phase of healing in Trem2 ؊/؊ mice showed a diminished burst of epithelial proliferation, increased expression of IFN-␥ and TNF-␣, diminished expression of IL-4 and IL-13, and increased markers of classical macrophage activation. Ablation of these cytokines in injured WT and Trem2 ؊/؊ mice demonstrated that their expression ultimately determined the rate and nature of wound healing. These studies show that Trem2 signaling is an important pathway to promote healing of wounds in the colon where stem cell replacement is necessary.biopsy injury ͉ epithelium ͉ macrophage ͉ stem cell ͉ wound healing

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Section: Efficient Wound Healing Did Not Require Neutrophils or Tlr-smentioning

confidence: 90%

Section: Efficient Wound Healing Did Not Require Neutrophils or Tlr-smentioning

confidence: 99%

Efficient colonic mucosal wound repair requires Trem2 signaling

Seno

Miyoshi²,

Brown³

et al. 2009

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

Self Cite

250

254

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“…Finally, although Myd88 -/-mice showed impaired regenerative IEC proliferation after DSSinduced epithelial injury [42,45], it is not clear whether this effect is due to defective MyD88 signaling in epithelial cells themselves or in other mucosal cells. Indeed, the proliferative IEC response after DSS injury is thought to rely on MyD88-dependent positioning of activated macrophages and COX2-producing stromal cells near the crypt base [50,51]. However, IEC-intrinsic MyD88 signaling could still play a role in these events, because bone marrow transfer experiments have suggested that recruitment and activation of macrophages depends on TLR4 signaling in IECs [52].…”

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

confidence: 99%

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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“…Identifying these MyD88-dependent processes will be an exciting avenue for future research. It would also be important to investigate whether the mechanism described by Brown et al (3) operates in other parts of the colon and the small intestine.…”

Section: Innate Immune Recognition Of the Commensal Microflora As A Cmentioning

confidence: 99%