The Role of TSLP in Atopic Dermatitis: From Pathogenetic Molecule to Therapeutical Target.

Atopic dermatitis (AD) is a kind of chronic skin disease with inflammatory infiltration, characterized by skin barrier dysfunction, immune response dysregulation, and skin dysbiosis. Thymic stromal lymphopoietin (TSLP) acts as a regulator of immune response, positively associated with AD deterioration. Mainly secreted by keratinocytes, TSLP interacts with multiple immune cells (including dendritic cells, T cells, and mast cells), following induction of Th2-oriented immune response during the pathogenesis of AD. This article primarily focuses on the TSLP biological function, the relationship between TSLP and different cell populations, and the AD treatments targeting TSLP.

Acacia catechu (L.f.) Willd and Scutellaria baicalensis Georgi extracts suppress LPS-induced pro-inflammatory responses through NF-кB, MAPK, and PI3K-Akt signaling pathways in alveolar epithelial type II cells.

Acacia catechu (L.f.) Willd (ACW) and Scutellaria baicalensis Georgi (SBG) are one of the most famous couplet Chinese medicines, widely used for treating infantile cough, phlegm, and fever caused by pulmonary infection. However, the underlying molecular mechanism of their anti-inflammatory activity has not been determined. The aim of this study was to evaluate the protective effect of this couplet Chinese medicines (ACW-SBG) on lipopolysaccharide (LPS)-induced inflammatory responses in acute lung injury (ALI) model of rats and the potential molecular mechanisms responsible for anti-inflammatory activities in alveolar epithelial type II cells (AEC-II). Standardization of the 70% ethanol extract of ACW and SBG was performed by using a validated reversed-phase high-pressure liquid chromatography method. Rats were pretreated with ACW-SBG for 7 days prior to LPS challenge. We assessed the effects of ACW-SBG on the LPS-induced production of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) in the bronchoalveolar lavage fluid (BALF). The wet-to-dry weight ratio was calculated, and hematoxylin and eosin staining of lung tissue was performed. Cell viability of AEC-II was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Real-time quantitative reverse transcription polymerase chain reaction assay was carried out to quantify the relative gene expression of TNF-α and IL-1ß in AEC-II. The western blotting analysis was executed to elucidate the expression of mediators linked to nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3 kinase-protein kinase B (PI3K-Akt) signaling pathways. ACW-SBG significantly decreased lung wet-to-dry weight ratio, ameliorated LPS-induced lung histopathological changes, and reduced the release of inflammatory mediators such as TNF-α and IL-1ß in BALF. In AEC-II, we found that the expression of TNF-α mRNA was also inhibited by ACW-SBG. ACW-SBG blocked NF-κB activation by preventing the phosphorylation of NF-κB (p65) as well as the phosphorylation and degradation of the inhibitor of kappa B kinase. ACW-SBG extracts also inhibited the phosphorylation of respective MAPKs (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) as well as Akt. The present study demonstrated that ACW-SBG played a potent anti-inflammatory role in LPS-induced ALI in rats. The potential molecular mechanism was involved in attenuating the NF-κB, MAPKs, and PI3K-Akt signaling pathways in LPS-induced AEC-II.

D-Mannose ameliorates DNCB-induced atopic dermatitis in mice and TNF-α-induced inflammation in human keratinocytes via mTOR/NF-κB pathway.

D-mannose is a C-2 epimer of glucose, widely distributed in nature. Atopic dermatitis (AD) is a chronic inflammatory disease characterized by repetitious itching. The present study aimed to explore the protective effect and the underlying mechanism of D-mannose against the development of atopic dermatitis. We tested the effect of D-mannose by establishing DNCB (2,4-dinitrochlorobenzene)-induced AD mice models in vivo and culturing keratinocytes (HaCaT and NHEK) in vitro. The skin lesion severity was evaluated by histochemical staining. Cytokine expression levels were measured by real-time PCR and ELISA assay. The expression of the mammalian target of rapamycin (mTOR)/ nuclear transcription factor κB (NF-κB)-signaling-related molecules were determined by western blotting. Here, we found that topical supplementation of D-mannose remarkably attenuated skin lesions and recovered skin barrier function in AD mice model induced by DNCB. Furthermore, in vivo and in vitro experiments indicated that D-mannose inhibited tumor necrosis factor-α (TNF-α)-mediated increased expression of inflammatory cytokines. D-mannose also markedly downregulated TNF-α-stimulated activation of mTOR/NF-κB signaling pathway that was crucial for regulating the inflammatory condition. However, these effects were abolished by treatment with inhibitors of mTOR or NF-κB in HaCaT and NHEK. As far as we know, this is the first study uncovering the effective role of D-mannose via skin topical application. We found that D-mannose plays a regulatory role on inflammatory keratinocytes, suggesting its therapeutic utilization as a potential drug against atopic dermatitis.

Single cell transcriptional zonation of human psoriasis skin identifies an alternative immunoregulatory axis conducted by skin resident cells.

Psoriasis is the most common skin disease in adults. Current experimental and clinical evidences suggested the infiltrating immune cells could target local skin cells and thus induce psoriatic phenotype. However, recent studies indicated the existence of a potential feedback signaling loop from local resident skin cells to infiltrating immune cells. Here, we deconstructed the full-thickness human skins of both healthy donors and patients with psoriasis vulgaris at single cell transcriptional level, and further built a neural-network classifier to evaluate the evolutional conservation of skin cell types between mouse and human. Last, we systematically evaluated the intrinsic and intercellular molecular alterations of each cell type between healthy and psoriatic skin. Cross-checking with psoriasis susceptibility gene loci, cell-type based differential expression, and ligand-receptor communication revealed that the resident psoriatic skin cells including mesenchymal and epidermis cell types, which specifically harbored the target genes of psoriasis susceptibility loci, intensively evoked the expression of major histocompatibility complex (MHC) genes, upregulated interferon (INF), tumor necrosis factor (TNF) signalling and increased cytokine gene expression for primarily aiming the neighboring dendritic cells in psoriasis. The comprehensive exploration and pathological observation of psoriasis patient biopsies proposed an uncovered immunoregulatory axis from skin local resident cells to immune cells, thus provided a novel insight for psoriasis treatment. In addition, we published a user-friendly website to exhibit the transcriptional change of each cell type between healthy and psoriatic human skin.

Fluorescence detection of glutathione S-transferases in a low GSH level environment.

Glutathione S-transferases (GSTs) play crucial roles in the detoxification process and the development of drug-resistance and are proved to be important markers for various tumors. Different from the previous probes, we developed a fluorescent probe enabling the detection of intracellular GSTs in a low GSH level environment by pre-treatment of the cells with thiol-scavengers.