Effects of systemic pretreatment with <scp>CpG</scp> oligodeoxynucleotides on skin wound healing in mice

Hergert, B; Grambow, Eberhard; Butschkau, Antje; Vollmar, Brigitte

doi:10.1111/wrr.12084

Cited by 9 publications

(12 citation statements)

References 29 publications

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“…They showed upregulated M1 marker, NOS2, and decreased M2 markers, Arg1 and CD163. This M1 phenotype is different from what is seen when mice are pretreated with CpG systemically 6 days before wound healing, where a marked increase in M2 macrophage marker RELM‐a is seen in association with accelerated wound healing . In another study in which CpG was administered topically, increased IL‐12 was seen more typical of an M1 response .…”

Section: Discussionmentioning

confidence: 80%

“…However, our data not surprisingly clearly show dermal macrophages take up and respond to CpG indicating they have these receptors. Keratinocytes also appear to express TLR9 though perhaps at lower levels . Subcutaneous osmotic pump delivery clearly favours delivery to dermal and subdermal tissues, and CpG may not reach the epidermis in adequate concentration to have an effect on this cell layer in our model.…”

Section: Discussionmentioning

confidence: 84%

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CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin

Mathes

Rice

Affandi

et al. 2015

Experimental Dermatology

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Toll-like receptor 9 (TLR9) drives innate immune responses after recognition of foreign or endogenous DNA containing unmethylated CpG motifs. DNA-mediated TLR9 activation is highly implicated in the pathogenesis of several autoimmune skin diseases, yet its contribution to the inflammation seen in these diseases remains unclear. In this study, TLR9 ligand, CpGB DNA, was administered to mice via a subcutaneous osmotic pump with treatment lasting 1 or 4 weeks. Gene expression and immunofluorescence analyses were used to determine chemokine expression and cell recruitment in the skin surrounding the pump outlet. CpGB DNA skin treatment dramatically induced a marked influx of CD11b+ F4/80+ macrophages, increasing over 4 weeks of treatment, and induction of IFNγ and TNFα expression. Chemokines, CCL2, CCL4, CCL5, CXCL9 and CXCL10, were highly induced in CpGB DNA-treated skin, although abrogation of these signalling pathways individually did not alter macrophage accumulation. Flow cytometry analysis showed that TLR9 activation in the skin increased circulating CD11b+ CD115+ Ly6Chi inflammatory monocytes following 1 week of CpGB DNA treatment. Additionally, skin-resident CD11b+ cells were found to initially take up subcutaneous CpGB DNA and propagate the subsequent immune response. Using diphtheria toxin-induced monocyte depletion mouse model, gene expression analysis demonstrated that CD11b+ cells are responsible for the CpGB DNA-induced cytokine and chemokine response. Overall, these data demonstrate that chronic TLR9 activation induces a specific inflammatory response, ultimately leading to a striking and selective accumulation of macrophages in the skin.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 84%

CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin

Mathes

Rice

Affandi

et al. 2015

Experimental Dermatology

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“…CpG ODN is considered as a TLR9 agonists and has been reported to activate the immune system and possess potential usage as vaccine adjuvant or immunotherapy for cancers . Recently, several studies demonstrate that treatment with CpG ODN improves skin wound healing in primates and mice …”

Section: Introductionmentioning

confidence: 99%

A C‐type CpG ODN accelerates wound healing via regulating fibroblasts and immune response

Zuo

et al. 2018

J of Cellular Biochemistry

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Abolished or delayed wound healing is a serious problem in clinical surgery, therefore, the new therapy for wound healing is needed. Synthetic oligodeoxynucleotides containing one or more CpG motifs (CpG ODN) has been reported to activate the immune system and improves skin wound healing. The aim of the present study was to evaluate the role of a new C‐type CpG ODN in wound healing. We found that the CpG ODN promoted cell proliferation and collagen I production in human skin fibroblasts cells. Besides, we also investigated the effect of CpG ODN on the activation of immune cells. The macrophages and plasmacytoid dendritic cells (pDCs) were incubated with CpG ODN. CpG ODN activated macrophage and pDCs via regulating TLR9/MyD88/NF‐κB pathway and TLR9/MyD88/IRF7 pathway, respectively. To further evaluate the effect of CpG ODN on wound healing in vivo a wound healing model was established in mice. The results showed that CpG ODN treatment accelerated wound healing in mice. CpG ODN increased cytokines secretion in wound skin and elevated the ratio of CD4 + and CD8 + T cells in the spleen. Our results showed that CpG ODN accelerated wound healing, which was partly due to the regulation of fibroblasts and immune response. The findings suggested that the CpG ODN might be a proper medicament for the treatment of wound healing.

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“…RELM-β belongs to a family of cysteine-rich secretory molecules initially described to control insulin resistance in rodents [ 26 , 27 ]. Interestingly, RELM proteins have been shown to modulate inflammation and wound healing processes [ 24 , 28 , 29 ]. RELM-β is produced solely by goblet cells, and is induced in the intestines of germfree mice following their colonization by commensal bacteria [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Goblet Cell Derived RELM-β Recruits CD4+ T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation

et al. 2015

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Enterohemorrhagic Escherichia coli and related food and waterborne pathogens pose significant threats to human health. These attaching/effacing microbes infect the apical surface of intestinal epithelial cells (IEC), causing severe diarrheal disease. Colonizing the intestinal luminal surface helps segregate these microbes from most host inflammatory responses. Based on studies using Citrobacter rodentium, a related mouse pathogen, we speculate that hosts rely on immune-mediated changes in IEC, including goblet cells to defend against these pathogens. These changes include a CD4+ T cell-dependent increase in IEC proliferation to replace infected IEC, as well as altered production of the goblet cell-derived mucin Muc2. Another goblet cell mediator, REsistin-Like Molecule (RELM)-β is strongly induced within goblet cells during C. rodentium infection, and was detected in the stool as well as serum. Despite its dramatic induction, RELM-β’s role in host defense is unclear. Thus, wildtype and RELM-β gene deficient mice (Retnlb -/-) were orally infected with C. rodentium. While their C. rodentium burdens were only modestly elevated, infected Retnlb -/- mice suffered increased mortality and mucosal ulceration due to deep pathogen penetration of colonic crypts. Immunostaining for Ki67 and BrDU revealed Retnlb -/- mice were significantly impaired in infection-induced IEC hyper-proliferation. Interestingly, exposure to RELM-β did not directly increase IEC proliferation, rather RELM-β acted as a CD4+ T cell chemoattractant. Correspondingly, Retnlb -/- mice showed impaired CD4+ T cell recruitment to their infected colons, along with reduced production of interleukin (IL)-22, a multifunctional cytokine that directly increased IEC proliferation. Enema delivery of RELM-β to Retnlb -/- mice restored CD4+ T cell recruitment, concurrently increasing IL-22 levels and IEC proliferation, while reducing mucosal pathology. These findings demonstrate that RELM-β and goblet cells play an unexpected, yet critical role in recruiting CD4+ T cells to the colon to protect against an enteric pathogen, in part via the induction of increased IEC proliferation.

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Effects of systemic pretreatment with CpG oligodeoxynucleotides on skin wound healing in mice

Cited by 9 publications

References 29 publications

CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin

CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin

A C‐type CpG ODN accelerates wound healing via regulating fibroblasts and immune response

Goblet Cell Derived RELM-β Recruits CD4+ T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation

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