Persistent and impaired inflammation impedes tissue healing and is a characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. In this study, we show that in human wound-edge keratinocytes, the expressions of microRNA (miR)-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17w92 cluster, are upregulated during wound repair. However, their levels are lower in chronic ulcers than in acute wounds at the proliferative phase. Conditional knockout of miR-17w92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17w92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-kB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines and cytokines by keratinocytes. Thus, miR-19a/b and miR-20a being crucial regulators of wound inflammation, the lack thereof may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.

Objectives:To study the demographic and clinical features of infantile hemangioma in China; to learn in more detail the risk factors for developing this disease; and to identify clinical characteristics associated with complications, associated risks, and the need for systemic treatment.Design: A case-control study of 1832 prospectively enrolled children with hemangiomas and 1832 controls matched for age, sex, region, and hospital attending the dermatology department between 2005 and 2008.Setting: Two large hospitals in central south China.Patients: A total of 1832 children with hemangiomas. Main Outcome Measures:Demographic and clinical presentations were summarized and compared with data from previous studies of hemangiomas. Predictive clinical factors for complications and/or treatment and potential risk factors for infantile hemangioma were analyzed by logistic regression. Results:The clinical features of our study patients were different from those of other race/ethnicity groups reported by previous studies with regard to the morphologic subtypes, complications, and predictors for complications and/ or oral corticosteroid treatment. After adjustment, significant risk factors for hemangiomas included lower level of maternal education (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.57-0.66), mother engaged in manual labor (OR, 1.29; 95% CI, 1.12-1.48), multiple gestation (OR, 1.20; 95% CI,1.05-1.36), maternal medication use during the periconceptional period (OR, 2.08; 95% CI, 1.88-2.31), and a positive family history of hemangiomas (OR, 1.55; 95% CI, 1.40-1.72). Conclusion:Besides yielding several new findings with respect to risk factors for hemangiomas, the current study also suggests that the Chinese clinical features of hemangiomas are somewhat different epidemiologically from those in the West.

T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on dendritic cells (DC) and macrophages, plays an essential role in regulating immune responses. Langerhans cells (LC), which are the sole DC subpopulation residing at the epidermis, are potent mediators of immune surveillance and tolerance. However, the significance of TIM-4 on epidermal LCs, along with other cutaneous DCs, remains totally unexplored. For the first time, we discovered that epidermal LCs expressed TIM-4 and displayed an increased level of TIM-4 expression upon migration. We also found that dermal CD207+ DCs and lymph node (LN) resident CD207−CD4+ DCs highly expressed TIM-4, while dermal CD207− DCs and LN CD207−CD4− DCs had limited TIM-4 expressions. Using TIM-4-deficient mice, we further demonstrated that loss of TIM-4 significantly upregulated the frequencies of epidermal LCs and LN resident CD207−CD4+ DCs. In spite of this, the epidermal LCs of TIM-4-deficient mice displayed normal phagocytic and migratory abilities, comparable maturation status upon the stimulation as well as normal repopulation under the inflamed state. Moreover, lack of TIM-4 did not affect dinitrofluorobenzene-induced contact hypersensitivity response. In conclusion, our results indicated that TIM-4 was differentially expressed in the distinct subsets of DCs in skin and skin-draining LNs, and specifically regulated epidermal LC and LN CD207−CD4+ DC homeostasis.

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.