Accelerated wound healing phenotype in Interleukin 12/23 deficient mice

Matias, Marie Anne Teresa J.; Saunus, Jodi M.; Ivanovski, Sašo; Walsh, L. J.; Farah, Camile S.

doi:10.1186/1476-9255-8-39

Cited by 29 publications

(33 citation statements)

References 45 publications

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“…35 Changes in angiogenic activity influence the rate of wound healing: suppression of angiogenesis delays and accelerated angiogenesis enhances wound healing. 36 We performed skin wound healing assays in WT, Thbs4 −/−; , and mutTSP-4 KI mice (Figure 3). Full thickness skin wounds (0.7 mm in diameter) were excised on the back of mice and allowed to heal uncovered over time.…”

Section: Resultsmentioning

confidence: 99%

Proangiogenic Properties of Thrombospondin-4

Muppala

Frolova

Xiao

et al. 2015

ATVB

113

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Objective Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis. Approach and Results The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using Thbs4−/−; mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in Thbs4−/−; mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from Thbs4−/−; mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin and gabapentin α2 receptor α2δ-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4. Conclusion TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.

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Section: Resultsmentioning

confidence: 99%

Proangiogenic Properties of Thrombospondin-4

Muppala

Frolova

Xiao

et al. 2015

ATVB

113

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“…For example, IL‐17 produced by inflammatory infiltrates after wounding caused a delay in wound closure, while an anti‐IL‐17 blocking antibody restored wound closure 44 . Similarly, wound healing was accelerated in Il‐17 −/− mice 44 and in Il‐12p40 −/− mice 45 . Consistent with our observation of selective poly(IC)‐inducible IL‐23p19 mRNA expression in keratinocytes, IL‐23p19 was also reported to be selectively upregulated in UV‐damaged keratinocytes 46 .…”

Section: Discussionmentioning

confidence: 99%

TLR3 drives IRF6‐dependent IL‐23p19 expression and p19/EBI3 heterodimer formation in keratinocytes

et al. 2015

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Interferon regulatory factor (IRF) family members impart cell-type specificity to toll-like receptor (TLR) signalling, and we recently identified a role for IRF6 in TLR2 signalling in epithelial cells. TLR3 has a well-characterized role in wound healing in the skin, and here, we examined TLR3-dependent IRF6 functions in human keratinocytes. Primary keratinocytes responded robustly to the TLR3 agonist poly(IC) with upregulation of mRNAs for interferon-β (IFN-β), the interleukin-12 (IL-12) family member IL-23p19 and the chemokines IL-8 and chemokine (C-C motif) ligand 5 (CCL5). Silencing of IRF6 expression enhanced poly(IC)-inducible IFN-β mRNA levels and inhibited poly(IC)-inducible IL-23p19 mRNA expression in primary keratinocytes. Consistent with these data, co-transfection of IRF6 increased poly(IC)-inducible IL-23p19 promoter activity, but inhibited poly(IC)-inducible IFN-β promoter activity in reporter assays. Surprisingly, poly(IC) did not regulate IL-12p40 expression in keratinocytes, suggesting that TLR3-inducible IL-23p19 may have an IL-23-independent function in these cells. The only other IL-12 family member that was strongly poly(IC) inducible was EBI3, which has not been shown to heterodimerize with IL-23p19. Both co-immunoprecipitation and proximity ligation assays revealed that IL-23p19 and EBI3 interact in cells. Co-expression of IL-23p19 and EBI3, as compared with IL-23p19 alone, resulted in increased levels of secreted IL-23p19, implying a functional role for this heterodimer. In summary, we report that IRF6 regulates a subset of TLR3 responses in human keratinocytes, including the production of a novel IL-12 family heterodimer (p19/EBI3). We propose that the TLR3-IRF6-p19/ EBI3 axis may regulate keratinocyte and/or immune cell functions in the context of cell damage and wound healing in the skin.

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“…IL‐12‐expressing tumor cells show low metastasis ability. In fact, IL‐12/23 deficient endothelial cells showed rapid wound healing . Thus, high levels of IL‐12p40 in patients with TAK may prevent endothelial cells from healing from inflammation.…”

Section: Basicsmentioning

confidence: 99%

Recent advances in Takayasu arteritis

2014

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Takayasu arteritis (TAK) is a relatively rare systemic vasculitis mainly affecting the aorta and its large branches. While patients with TAK are more frequently observed in Asian countries, we can find patients with TAK all over the world. This limited number of patients has made it difficult to collect large numbers of patients and perform detailed studies. However, recent progresses have led to the identification of susceptibility genes and novel susceptibility human leukocyte antigen (HLA) alleles as well as accumulation of clues for the pathophysiology of TAK. IL12B was shown to be a susceptibility gene beyond ethnicity. MLX and FCGR2A/3A were shown to be associated with TAK in Japanese and Turkish/American populations, respectively. HLA-B*52:01 and *67:01 are susceptibility alleles to TAK, and the 171st and 67th amino acid residues of HLA-B protein are suggested important for TAK susceptibility. HLA-DQB1/DRB1 is recently reported as an independent susceptibility locus. Although there are no standardized serum markers or composite measures for disease activity of TAK, Japanese and Italian groups showed pentraxin 3 as a novel biomarker for detecting and monitoring patients with TAK. Recently, an Indian group proposed a novel scoring system called ITAS to evaluate disease activity of TAK. Standardization of assessing disease activity would lead to clinical studies with high quality. Several groups reported results of treatment for refractory TAK with biological agents targeting tumor necrosis factor or interleukin-6R. The recent accumulation of research data should improve understanding of the basic pathophysiology of TAK and lead to better management of patients with TAK.

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Accelerated wound healing phenotype in Interleukin 12/23 deficient mice

Cited by 29 publications

References 45 publications

Proangiogenic Properties of Thrombospondin-4

Proangiogenic Properties of Thrombospondin-4

TLR3 drives IRF6‐dependent IL‐23p19 expression and p19/EBI3 heterodimer formation in keratinocytes

Recent advances in Takayasu arteritis

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