MicroRNA-34 Family Enhances Wound Inflammation by Targeting LGR4

Abstract

Venous ulcers are the most common type of human chronic nonhealing wounds and are stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remain elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs, in the pathogenesis of venous ulcers. We found that both microRNA (miR)-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of venous ulcers compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wildtype mice, miR-34aemimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 functions, LGR4 was identified as a direct target mediating the proinflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 knockout mice. Mechanistically, the miR-34eLGR4 axis regulated GSK-3beinduced p65 serine 468 phosphorylation, changing the activity of the NF-kB signaling pathway. Collectively, the miR-34eLGR4 axis was shown to regulate keratinocyte inflammatory response, the deregulation of which may play a pathological role in venous ulcers.

SIRT3 deficiency delays diabetic skin wound healing via oxidative stress and necroptosis enhancement

“…The process of skin trauma is essentially the damage by imbalance of skin internal environment with harmful stimulation as oxidative stress, inflammation, radiation etc During wound healing, various inflammatory cells, such as macrophages, neutrophils, even endothelial cells and fibroblasts, produce active oxygen and free radicals . Although appropriate amount of free radicals are beneficial to promote wound healing, too much active oxygen suppresses the migration and proliferation of repair cells, inhibits extracellular matrix synthesis and finally delays wound healing .…”

The Immune Functions of Keratinocytes in Skin Wound Healing

“…Promotes inflammatory chemokine and cytokine production by keratinocytes LGR4 17 [146] hsa-miR-203a-3p Suppresses skin re-epithelialization RAN 18 , RAPH1 19 , and IL-8 [147,148] hsa-miR- 21-5p Promotes skin re-epithelialization TIMP3 20 and TIAM1 21 [149] hsa-miR-130a-3p…”

“…Multiple miRNAs are dysregulated in human chronic wounds and contribute to delayed wound healing through regulating keratinocyte immune functions, e.g., miR-132, miR-146, miR-34a/c, miR-19a/b, miR-20a, miR-203, miR-21, and miR-130 [127,[144][145][146]148,150] (Table 2). The miR-132 expression is significantly reduced in human diabetic ulcers compared with normal acute wounds [178].…”

Advances and Impact of Antioxidant Hydrogel in Chronic Wound Healing

“…Acute wounds, also known as normal wounds, are usually caused by mechanical, burn, or chemical injuries . The wounds can be completely healed with the smallest scar, and the healing time is usually 8–12 weeks …”

“…[24][25][26] The wounds can be completely healed with the smallest scar, and the healing time is usually 8-12 weeks. [27,28] As we all know, healthy skin mainly includes epidermis, dermis, and subcutaneous. [29] 1) The epidermis is the outermost barrier.…”