Skin wound macrophages are key regulators of skin repair and their dysfunction causes chronic, non-healing skin wounds. Peroxisome proliferator-activated receptor gamma (PPARγ) regulates pleiotropic functions of macrophages, but its contribution in skin wound healing is poorly defined. We observed that macrophage PPARγ expression was upregulated during skin wound healing. Furthermore, macrophage PPARγ deficiency (PPARγ-knock out (KO)) mice exhibited impaired skin wound healing with reduced collagen deposition, angiogenesis and granulation formation. The tumor necrosis factor alpha (TNF-α) expression in wounds of PPARγ-KO mice was significantly increased and local restoration of TNF-α reversed the healing deficit in PPARγ-KO mice. Wound macrophages produced higher levels of TNF-α in PPARγ-KO mice compared with control. In vitro, the higher production of TNF-α by PPARγ-KO macrophages was associated with impaired apoptotic cell clearance. Correspondingly, increased apoptotic cell accumulation was found in skin wound of PPARγ-KO mice. Mechanically, peritoneal and skin wound macrophages expressed lower levels of various phagocytosis-related molecules. In addition, PPARγ agonist accelerated wound healing and reduced local TNF-α expression and wound apoptotic cells accumulation in wild type but not PPARγ-KO mice. Therefore, PPARγ has a pivotal role in controlling wound macrophage clearance of apoptotic cells to ensure efficient skin wound healing, suggesting a potential new therapeutic target for skin wound healing.

During neurogenesis, specific transcription factors are needed to repress neuronal genes in nonneuronal cells to ensure precise development. Repressor element-1 binding transcription factor (REST), or neuron-restrictive silencer factor (NRSF), has been shown to be an important regulator for the establishment of neuronal specificity. It restricts the expression of neuronal genes by binding to the neuron-restrictive silencer element (NRSE/RE1) domain in neuron-specific genes. REST/NRSF regulates many target genes in stem cells, nonneural cells, and neurons, which are involved in neuronal differentiation, axonal growth, vesicular transport, and release as well as ionic conductance. However, it is also regulated by some cytokines/regulators such as epigenetic factors (microRNAs) and even its truncated isoform. REST/NRSF is widely detected in brain regions and has been shown to be highly expressed in nonneuronal cells, but current findings also reveal that, at least in the human brain, it is also highly expressed in neurons and increases with ageing. However, its loss in expression and cytoplasmic translocation seems to play a pivotal role in several human dementias. Additionally, REST/NRSF knockdown leads to malformations in nerve and nonneural tissues and embryonic lethality. Altered REST/NRSF expression has been not only related to deficient brain functions such as neurodegenerative diseases, mental disorders, brain tumors, and neurobehavioral disorders but also highly correlated to brain injuries such as alcoholism and stroke. Encouragingly, several compounds such as valproic acid and X5050 that target REST/NRSF have been shown to be clinically effective at rescuing seizures or Niemann-Pick type C disease. Surprisingly, studies have also shown that REST/NRSF can function as an activator to induce neuronal differentiation. These findings strongly indicate that REST/NRSF is not only a classical repressor to maintain normal neurogenesis, but it is also a fine fundamental protector against neurodegeneration and other disorders and may be a novel potent therapeutic target for neural disturbances.

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In the hippocampus, local estrogens (E) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E, and E induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics.