Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing

Ishida, Yuko; Kimura, Akihiko; Kuninaka, Yumi; Inui, Makoto; Matsushima, Kouji; Mukaida, Naofumi; Kondo, Toshikazu

doi:10.1172/jci43027

Cited by 140 publications

(137 citation statements)

References 55 publications

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“…Interestingly, interaction of Ccl5 with its receptor Ccr5 was found to play a pivotal role in mouse wound-healing process. 20 Cxcl11 shares its receptor Cxcr3 with Cxcl10 in recruitment of activated T cells. Recent studies indicate that CXCR3 signaling plays a critical role in the process of cutaneous wound healing.…”

Section: Chemical Chaperone Lewisite Antidotesmentioning

confidence: 99%

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Srivastavá

Weng

et al. 2016

The American Journal of Pathology

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Lewisite is a potent arsenic-based chemical warfare agent known to induce painful cutaneous inflammation and blistering. Only a few modestly effective antidotes have so far been described in the literature. However, the discovery of effective antidotes for lewisite was hampered by the paucity of the exact molecular mechanism underlying its cutaneous pathogenesis. We investigated the molecular mechanism underlying lewisite-induced cutaneous blistering and inflammation and describe its novel antidotes. On the basis of our initial screening, we used a highly sensitive murine model that recapitulates the known human pathogenesis of arsenicals-induced cutaneous inflammation and blistering. Topically administered lewisite induced potent acute inflammation and microvesication in the skin of Ptch1 þ/À /SKH-1 mice. Even at a very low dose, lewisite up-regulates unfolded protein response signaling, inflammatory response, and apoptosis. These cutaneous lesions were associated with production of reactive oxygen species and extensive apoptosis of the epidermal keratinocytes. We confirmed that activation of reactive oxygen speciesedependent unfolded protein response signaling is the underlying molecular mechanism of skin damage. Similar alterations were noticed in lewisitetreated cultured human skin keratinocytes. We discovered that chemical chaperone 4ephenyl butyric acid and antioxidant N-acetylcysteine, which significantly attenuate lewisite-mediated skin injury, can serve as potent antidotes. These data reveal a novel molecular mechanism underlying the cutaneous pathogenesis of lewisite-induced lesions. We also identified novel potential therapeutic targets for lewisite-mediated cutaneous injury.

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Section: Chemical Chaperone Lewisite Antidotesmentioning

confidence: 99%

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Srivastavá

Weng

et al. 2016

The American Journal of Pathology

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“…60 However, during the excisional skin wound repair process, CCL5, through CCR5, promotes bone marrowederived progenitor cells homing to wound sites, hence accelerating wound healing in mice. 61 The suppressed expression of CXCL5 and CCL5 may contribute to the defects in polymorphonuclear neutrophil infiltration and/or progenitor cell generation observed in DM wounded corneas.…”

Section: Il-1ra and Diabetic Cornea Wound Healingmentioning

confidence: 99%

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

Yan

Gao

Sun

et al. 2016

The American Journal of Pathology

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fanxq@sh163. net.Patients with diabetes mellitus often develop corneal complications and delayed wound healing. How diabetes might alter acute inflammatory responses to tissue injury, leading to delayed wound healing, remains mostly elusive. Using a streptozotocin-induced type I diabetes mellitus mice and corneal epithelium-debridement wound model, we discovered that although wounding induced marked expression of IL-1b and the secreted form of IL-1 receptor antagonist (sIL-1Ra), diabetes suppressed the expressions of sIL-1Ra but not IL-1b in healing epithelia and both in whole cornea. In normoglycemic mice, IL-1b or sIL-1Ra blockade delayed wound healing and influenced each other's expression. In diabetic mice, in addition to delayed reepithelization, diabetes weakened phosphatidylinositol 3-kinaseeAkt signaling, caused cell apoptosis, diminished cell proliferation, suppressed neutrophil and natural killer cell infiltrations, and impaired sensory nerve reinnervation in healing mouse corneas. Local administration of recombinant IL-1Ra partially, but significantly, reversed these pathological changes in the diabetic corneas. CXCL10 was a downstream chemokine of IL-1beIL-1Ra, and exogenous CXCL10 alleviated delayed wound healing in the diabetic, but attenuated it in the normal corneas. In conclusion, the suppressed early innate/inflammatory responses instigated by the imbalance between IL-1b and IL-1Ra is an underlying cause for delayed wound healing in the diabetic corneas. Local application of IL-1Ra accelerates reepithelialization and may be used to treat chronic corneal and potential skin wounds of diabetic patients. (Am J Pathol 2016 http://dx

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“…CCL5 is a potent chemoattractant for many cell types, such as monocytes, NK cells (74,75), memory T cells (75), eosinophils (76), and dendritic cells (77), many of which are present in KS lesions. CCL5 levels correlated with neovascularization in a mouse model of angiogenesis (78), and CCL5 is thought to play a pivotal role in the recruitment of endothelial progenitors that are essential for neovascularization through interaction with CCR5 (79). KS is characterized by chronic inflammation and neoangiogenesis, and the observed kaposin B-induced increase in CCL5 has the potential to mediate these effects and contribute significantly to KS tumorigenesis.…”

Section: Figmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

King

2013

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1␤), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.

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Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing

Abstract: BM-derived endothelial progenitor cells (EPCs

Cited by 140 publications

References 55 publications

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

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