Scutellaria baicalensis (Huang-Qin in Chinese medicine) produces bioactive 4′-deoxyflavones by a newly evolved metabolic pathway.

TSLP AhR IAId Tryptophan Epidermis Dermis AhRE TSLP IL-4,IL-5,IL-13,IL-22AD Background: Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. Objective: We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD.Methods: A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography-tandem mass spectrometry. A mouse model of calcipotriol (MC903)-induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)-null mice and keratinocyte cultures were used to investigate the mechanism.We thank Professor Shau-Ku Huang for helpful suggestions and reviewing the manuscript. Key messagesd Levels of microbial metabolites of Trp metabolism on skin surfaces of patients with AD were lower than those of healthy subjects.d IAId significantly attenuated skin inflammation in a mouse model of MC903-induced AD-like dermatitis.d IAId inhibited TSLP expression in keratinocytes in an AhR-dependent manner.

Our study demonstrated that CXCL16-CXCR6 mediates CD8 T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response activation.

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Background We previously reported that lymphocytopenia and T cell exhaustion is notable in acute COVID19 patients, especially in aged and severe cases. Thymosin alpha 1 (Tα1) had been used in the treatment of viral infections as an immune response modifier for many years. However, clinical benefits and mechanism of Tα1 supplement to COVID-19 are still unclear. Methods We retrospectively reviewed the clinical outcomes of 76 severe cases with COVID-19 admitted into two hospitals in Wuhan from December 2019 to March 2020. The thymus output in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients was measured by T cell receptor excision circles (TREC). The levels of T cell exhaustion markers PD-1 and Tim-3 on CD8+ T cells were detected by flow cytometry. Results Compared with untreated group, Tα1 treatment significantly reduces mortality of severe COVID-19 patients (11.11% vs. 30.00%, p=0.044). Tα1 timely enhances blood T cell numbers in COVID-19 patients with severe lymphocytopenia (the counts of CD8+ T cells or CD4+ T cells in circulation lower than 400/μL or 650/μL, respectively). Under such conditions, Tα1 also successfully restores CD8+ and CD4+ T cell numbers in aged patients. Meanwhile, Tα1 reduces PD-1 and Tim-3 expression on CD8+ T cells from severe COVID-19 patients in comparison with untreated cases. It is of note that restoration of lymphocytopenia and acute exhaustion of T cells are roughly parallel to the rise of TRECs. Conclusions Tα1 supplement significantly reduce mortality of severe COVID-19 patients. COVID-19 patients with the counts of CD8+ T cells or CD4+ T cells in circulation lower than 400/μL or 650/μL, respectively, gain more benefits from Tα1. Tα1 reverses T cell exhaustion and recovers immune reconstitution through promoting thymus output during SARS-CoV-2 infection.

The gastrointestinal tract is the site of nutrient digestion and absorption and is also colonized by diverse, highly mutualistic microbes. The intestinal microbiota has diverse effects on the development and function of the gut-specific immune system, and provides some protection from infectious pathogens. However, interactions between intestinal immunity and microorganisms are very complex, and recent studies have revealed that this intimate crosstalk may depend on the production and sensing abilities of multiple bioactive small molecule metabolites originating from direct produced by the gut microbiota or by the metabolism of dietary components. Here, we review the interplay between the host immune system and the microbiota, how commensal bacteria regulate the production of metabolites, and how these microbiota-derived products influence the function of several major innate and adaptive immune cells involved in modulating host immune homeostasis.

Psoriasis, an immunological skin disease, is characterized by epidermal hyperproliferation, chronic inflammation, and an accumulation of infiltrating T cells. IL-17A is a key cytokine that has a critical role in the pathogenesis of psoriasis. Keratin 17 (K17) is strongly expressed in psoriatic lesions but not in normal skin. Thus, K17 expression is regarded as a hallmark of psoriasis. We previously reported that the K17/T cells/cytokine autoimmune loop was involved in psoriasis. However, the relationship between IL-17A and K17 has yet to be determined. In the present study, IL-17A-induced K17 expression was confirmed in cultured keratinocytes in both mRNA and protein levels. In addition, increased K17 expression was found in the epidermis of IL-17A-injected mouse skin. The regulatory mechanism of K17 expression was further investigated. We found that both the signal transducer and activator of transcription (STAT) 1 and STAT3 pathways were involved in the upregulation of K17 expression induced by IL-17A, and that such regulation could be partially suppressed by STAT1 or STAT3 small interfering RNA and inhibitor. Our data suggest that IL-17A can upregulate K17 expression in keratinocytes in a dose-dependent manner through STAT1- and STAT3-dependent mechanisms. The results indicate that IL-17A might be an important cytokine in the K17/T cells/cytokine autoimmune loop associated with psoriasis.

Psoriasis is characterized by resistance to infections, which is regulated by antimicrobial proteins. Whether antimicrobial proteins play a pathogenic role in psoriasis remains unclear. In this study, we aimed to elucidate the role of lipocalin-2 (Lcn2), an antimicrobial protein, in the pathogenesis of psoriasis. Our results showed that Lcn2 was highly expressed in the lesional skin of psoriatic patients. The neutralization of Lcn2 alleviated epidermal hyperplasia, inflammation, and especially neutrophil infiltration in an imiquimod-induced psoriasis-like murine model. In vitro, Lcn2 stimulated human neutrophils to produce vital proinflammatory mediators, such as IL-6, IL-8, tumor necrosis factor-α, and IL-1α via a specific receptor, 24p3R, on neutrophils, which consequently activated the downstream extracellular signal-regulated kinase-1/2 and p38-mitogen-activated protein kinase signaling pathways. Moreover, Lcn2-induced neutrophil chemotaxis was concentration dependent and mediated by the extracellular signal-regulated kinase-1/2 and p38-mitogen-activated protein kinase signaling pathways in vitro. Furthermore, we demonstrated that both keratinocytes and neutrophils were the sources of Lcn2 in the lesional skin of psoriatic patients. Taken together, these results suggest that Lcn2 is involved in the pathogenesis of psoriasis by modulating neutrophil function, and that it could serve as a potential target for treating psoriasis.