Efficient colonic mucosal wound repair requires Trem2 signaling.

Proc Natl Acad Sci U S A 2009 Jan 24;106(1):256-61. Epub 2008 Dec 24.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkühn. 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-gamma and TNF-alpha, 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.

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http://dx.doi.org/10.1073/pnas.0803343106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629230PMC
January 2009
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References

(Supplied by CrossRef)

Chang et al.
The American journal of anatomy 1971

Savage et al.
Annual review of microbiology 1977

Hooper et al.
Science 2001

Strober et al.
Annual review of immunology 2002

Elson et al.
Immunological reviews 2005

Rakoff-Nahoum et al.
Cell 2004

PNAS 2005

Fukata et al.
American Journal of Physiology - Gastrointestinal and Liver Physiology 2005

Martin et al.
Science 1997

Becker et al.
Immunity 2004

Becker et al.
Gut 2005

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