SOCS3 negatively regulates the gp130-STAT3 pathway in mouse skin wound healing.
Proliferation and differentiation of keratinocytes during wound healing are regulated by cytokines and chemokines, which are secreted by resident and inflammatory cells and activate the transcription factor signal transducer and activator of transcription (STAT)3. However, it is not clear to what extent STAT3 in keratinocytes is activated by gp130-containing receptors. We addressed this question genetically by deleting the suppressor of cytokine signaling (SOCS)3, a negative regulator of gp130-mediated STAT3 activation. Socs3 alleles flanked by loxP sites were deleted in mice with either an MMTV-Cre or K5-Cre transgene. While both transgenes are active in keratinocytes, the MMTV-Cre deletes floxed genes also in immune cells. Deletion of Socs3 using the MMTV-Cre transgene resulted in aberrant STAT3 activation, impaired wound healing, prolonged secretion of chemokines, a hyperproliferative epidermis, and neutrophil infiltration into wounds. Simultaneous deletion of the Socs3 and gp130 genes restored normal wound healing. Moreover, deletion of Socs3 only in keratinocytes caused impaired wound healing. These results demonstrate that wound healing is controlled in keratinocytes by the gp130-SOCS3-STAT3 pathway and an imbalance of this pathway results in delayed wound healing.
Zhu
Bing-Mei
BM
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ishida
Yuko
Y
Robinson
Gertraud W
GW
Pacher-Zavisin
Margit
M
Yoshimura
Akihiko
A
Murphy
Philip M
PM
Hennighausen
Lothar
L
D000818:Animals; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
C494200:Il6st protein, mouse; D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130