Blocking Microglial Proliferation by CSF-1R Inhibitor Does Not Alter the Neuroprotective Effects of Adoptive Regulatory T Cells in 3xTg Alzheimer's Disease Mice.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes cognitive impairment. Neuroinflammation induced by activated microglia exacerbates AD. Regulatory T cells (Tregs) play roles in limiting neuroinflammation by converting microglial polarization. Therefore, adoptive Treg therapy is considered an attractive option for neurodegenerative disorders. However, the mechanism underlying Treg therapy via microglial modulation is not fully understood. In this study, we sought to determine whether adoptively transferred Tregs were effective when microglia proliferation was inhibited by using GW2580, which is an inhibitor of CSF1R. We found that inhibition of microglial proliferation during Treg transfer did not alter the therapeutic effects of Tregs on cognitive deficits and the accumulation of Aß and pTAU in 3xTg-AD mice. The expression of pro- and anti-inflammatory markers in the hippocampus of 3xTg mice showed that GW2580 did not affect the inhibition of neuroinflammation by Treg transfer. Additionally, adoptively transferred Tregs were commonly detected in the brain on day 7 after transfer and their levels decreased slowly over 100 days. Our findings suggest that adoptively transferred Tregs can survive longer than 100 days in the brain, suppressing microglial activation and thus alleviating AD pathology. The present study provides valuable evidence to support the prolonged efficacy of adoptive Treg therapy in AD.

Transcriptome Analysis of Particulate Matter 2.5-Induced Abnormal Effects on Human Sebocytes.

Particulate matter 2.5 (PM2.5), an atmospheric pollutant with an aerodynamic diameter of <2.5 µm, can cause serious human health problems, including skin damage. Since sebocytes are involved in the regulation of skin homeostasis, it is necessary to study the effects of PM2.5 on sebocytes. We examined the role of PM2.5 via the identification of differentially expressed genes, functional enrichment and canonical pathway analysis, upstream regulator analysis, and disease and biological function analysis through mRNA sequencing. Xenobiotic and lipid metabolism, inflammation, oxidative stress, and cell barrier damage-related pathways were enriched; additionally, PM2.5 altered steroid hormone biosynthesis and retinol metabolism-related pathways. Consequently, PM2.5 increased lipid synthesis, lipid peroxidation, inflammatory cytokine expression, and oxidative stress and altered the lipid composition and expression of factors that affect cell barriers. Furthermore, PM2.5 altered the activity of sterol regulatory element binding proteins, mitogen-activated protein kinases, transforming growth factor beta-SMAD, and forkhead box O3-mediated pathways. We also suggest that the alterations in retinol and estrogen metabolism by PM2.5 are related to the damage. These results were validated using the HairSkin® model. Thus, our results provide evidence of the harmful effects of PM2.5 on sebocytes as well as new targets for alleviating the skin damage it causes.

Magnoliae Cortex Alleviates Muscle Wasting by Modulating M2 Macrophages in a Cisplatin-Induced Sarcopenia Mouse Model.

Cachexia causes high mortality, low quality of life, and rapid weight loss in cancer patients. Sarcopenia, a condition characterized by the loss of muscle, is generally present in cachexia and is associated with inflammation. M2 macrophages, also known as an anti-inflammatory or alternatively activated macrophages, have been shown to play a role in muscle repair. Magnoliae Cortex (M.C) is a widely used medicinal herb in East Asia reported to have a broad range of anti-inflammatory activities; however, the effects of M.C on sarcopenia and on M2 macrophage polarization have to date not been studied. This study was designed to investigate whether the oral administration of M.C could decrease cisplatin-induced sarcopenia by modulating M2 macrophage polarization in mice. C57BL/6 mice were injected intraperitoneally with cisplatin (2.5 mg/kg) to mimic chemotherapy-induced sarcopenia. M.C extract (50, 100, and 200 mg/kg) was administered orally every 3 days (for a total of 12 times). M.C (100 and 200 mg/kg) significantly alleviated the cisplatin-induced loss of body mass, skeletal muscle weight, and grip strength. In addition, M.C increased the expression of M2 macrophage markers, such as MRC1, CD163, TGF-ß, and Arg-1, and decreased the expression of M1-specific markers, including NOS2 and TNF-α, in skeletal muscle. Furthermore, the levels of like growth factor-1(IGF-1), as well as the number of M2a and M2c macrophages, significantly increased in skeletal muscle after M.C administration. M.C did not interfere with the anticancer effect of cisplatin in colon cancer. Our results demonstrated that M.C can alleviate cisplatin-induced sarcopenia by increasing the number of M2 macrophages. Therefore, our findings suggest that M.C could be used as an effective therapeutic agent to reverse or prevent cisplatin-induced sarcopenia.

Therapeutic effects of MEL-dKLA by targeting M2 macrophages in pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a progressive lung disease characterized by excessive extracellular matrix accumulation and myofibroblast proliferation with limited treatment options available. M2 macrophages are pivotal in pulmonary fibrosis, where they induce the epithelial-to-mesenchymal and fibroblast-to-myofibroblast transitions. In this study, we evaluated whether MEL-dKLA, a hybrid peptide that can eliminate M2 macrophages, could attenuate pulmonary fibrosis in a cell co-culture system and in a bleomycin-induced mouse model. Our findings demonstrated that the removal of M2 macrophages using MEL-dKLA stimulated reprogramming to an antifibrotic environment, which effectively suppressed epithelial-to-mesenchymal and fibroblast-to-myofibroblast transition responses in lung epithelial and fibroblast cells and reduced extracellular matrix accumulation both in vivo and in vitro. Moreover, MEL-dKLA exhibited antifibrotic efficacy without damaging tissue-resident macrophages in the bleomycin-induced mouse model. Collectively, our findings suggest that MEL-dKLA may be a new therapeutic option for the treatment of idiopathic pulmonary fibrosis.

Transcriptome analysis of airborne PM2.5-induced detrimental effects on human keratinocytes.

Ambient air pollution is becoming more severe worldwide, posing a serious threat to human health. Fine airborne particles of particulate matter (PM2.5) show higher cytotoxicity than other coarse fractions. Indeed, PM2.5 induces cardiovascular or respiratory damage; however, few studies have evaluated the detrimental effect of PM2.5 to normal human skin. We used a next-generation sequencing-based (RNA-Seq) method with transcriptome and Gene Ontology (GO) enrichment analysis to determine the harmful influences of PM2.5 on human normal epidermal keratinocytes. DAVID analysis showed that the most significantly enriched GO terms were associated with epidermis-related biological processes such as "epidermis development (GO: 0008544)" and "keratinocyte differentiation (GO: 0030216)", suggesting that PM2.5 has some deleterious effects to the human epidermis. In addition, Ingenuity Pathway Analysis predicted inflammation-related signaling as one of the major PM2.5-induced signaling pathways, and pro-inflammatory cytokines as upstream regulators with symptoms similar to psoriasis as downstream effects. PM2.5 caused considerable changes in the expression of pro-inflammatory cytokines and psoriatic skin disease-related genes, might lead to epidermal dysfunctions. Our results might help to understand the mechanism of air pollution-induced skin barrier perturbation and contribute to the development of a new strategy for the prevention or recovery of the consequent damage.