Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
J Dermatol Sci. 2014 Feb;73(2):117-24. doi: 10.1016/j.jdermsci.2013.10.009. Epub 2013 Oct 31.
Toll-like receptors (TLRs) have a crucial role in early host defense against invading pathogens. Recent studies suggest that TLRs play important roles in non-infections inflammation and tissue repair and regeneration.
To determine the roles of TLR2 and TLR4 in mouse wound healing using TLR2-deficient (TLR2(-/-)), TLR4-deficient (TLR4(-/-)), and TLR2/TLR4-deficient (TLR2/4(-/-)) mice.
Open wounds made in TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice were examined clinically and histologically. Cytokine expression in the wounded skin was also investigated. TGF-β production from macrophages stimulated by hyaluronan, a ligand for TLR2 and TLR4, was evaluated by real-time PCR.
Wound areas in TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice were larger than wild-type mice both at days 3 and 7 after wounding, accompanied by decreased numbers of infiltrating macrophages in the dermis and decreased TGF-β and CCL5 mRNA expression in the wounded skin. Immunohistochemistry showed decreased numbers of macrophages expressing TGF-β and reduced CCL5 expression by keratinocytes in the wounded skin from TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice compared to wild-type mice. Moreover, TGF-β production from macrophages induced by hyaluronan stimulation in vitro was significantly decreased in the absence of TLRs, especially TLR4. Interestingly, macrophages and wounded skin from TLR2(-/-) mice showed decreased TLR4 mRNA expression compared to wild-type mice, suggesting that the effect of TLR2 deficiency was at least partially dependent on decrease in TLR4. Topical application of TGF-β and CCL5 significantly improved wound healing in TLR-deficient mice.
TLR4, rather than TLR2, regulates wound healing through TGF-β and CCL5 expression.
Toll 样受体 (TLR) 在宿主抵御入侵病原体的早期防御中发挥关键作用。最近的研究表明，TLR 在非感染性炎症和组织修复与再生中发挥重要作用。
利用 TLR2 缺陷 (TLR2(-/-))、TLR4 缺陷 (TLR4(-/-)) 和 TLR2/TLR4 双缺陷 (TLR2/4(-/-)) 小鼠，确定 TLR2 和 TLR4 在小鼠伤口愈合中的作用。
临床和组织学检查 TLR2(-/-)、TLR4(-/-) 和 TLR2/4(-/-) 小鼠的开放性伤口。还研究了受伤皮肤中的细胞因子表达。通过实时 PCR 评估 TLR2 和 TLR4 配体透明质酸刺激的巨噬细胞产生 TGF-β 的情况。
TLR2(-/-)、TLR4(-/-) 和 TLR2/4(-/-) 小鼠的伤口面积在伤后 3 天和 7 天均大于野生型小鼠，真皮内浸润的巨噬细胞数量减少，受伤皮肤中 TGF-β 和 CCL5 mRNA 表达减少。免疫组织化学显示，与野生型小鼠相比，TLR2(-/-)、TLR4(-/-) 和 TLR2/4(-/-) 小鼠受伤皮肤中表达 TGF-β 的巨噬细胞数量减少，角质形成细胞中 CCL5 表达减少。此外，体外透明质酸刺激诱导的巨噬细胞 TGF-β 产生在 TLR 缺失时显著减少，尤其是 TLR4。有趣的是，与野生型小鼠相比，TLR2(-/-) 小鼠的巨噬细胞和受伤皮肤中 TLR4 mRNA 表达减少，表明 TLR2 缺乏的影响至少部分依赖于 TLR4 的减少。TGF-β 和 CCL5 的局部应用显著改善了 TLR 缺陷小鼠的伤口愈合。
TLR4 通过 TGF-β 和 CCL5 表达调节伤口愈合，而 TLR2 作用不大。
