SPRY1 Deficiency in Keratinocytes Induces Follicular Melanocyte Stem Cell Migration to the Epidermis through p53/Stem Cell Factor/C-KIT Signaling.

The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes (KCs). KCs and melanocytes respond to UV exposure by eliciting a tanning response. However, how KCs and melanocytes interact in the absence of UV exposure is unknown. In this study, we demonstrate that after SPRY1 knockout in epidermal KCs, melanocyte stem cells in the hair follicle exit the niche without depleting the pool of these cells. We also found that melanocyte stem cells migrate to the epidermis in a p53/stem cell factor/C-KIT-dependent manner induced by a tanning-like response resulting from SPRY1 loss in epidermal KCs. Once there, these cells differentiate into functional melanocytes. These findings provide an example in which the migration of melanocyte stem cells to the epidermis is due to loss of SPRY1 in epidermal KCs and show the potential for developing therapies for skin pigmentation disorders by manipulating melanocyte stem cells.

Glycyl-tRNA Synthetase Induces Psoriasis-Like Skin by Facilitating Skin Inflammation and Vascular Endothelial Cell Angiogenesis.

Psoriasis is characterized by excessive keratinocyte proliferation and immunocyte infiltration, but the underlying pathogenesis remains unclear. Aminoacyl-tRNA synthetases are universally expressed enzymes that catalyze the first step of protein synthesis. Glycyl-tRNA synthetase (GARS) is a member of the aminoacyl-tRNA synthetase family. In addition to its canonical function, we found that GARS was overexpressed in the serum and skin lesions of patients with psoriasis. Moreover, GARS was highly expressed in human skin keratinocytes, and GARS knockdown in keratinocytes suppressed cell proliferation and promoted apoptosis through NF-κB/MAPK signaling pathway. Moreover, intradermal injection of recombinant GARS protein caused skin thickening, angiogenesis, and IFN/TNF-driven skin inflammation. Intriguingly, the reported functional receptor for GARS, cadherin 6 (CDH6), was specifically expressed in vascular endothelial cells, and we found that keratinocyte-derived GARS promotes inflammation and angiogenesis of vascular endothelial cells through CDH6. In addition, intradermal injection of GARS aggravated the phenotype and angiogenesis in imiquimod-induced psoriasiform dermatitis models, whereas the psoriatic phenotype and angiogenesis were relieved after knockdown of GARS by adeno-associated virus. Taken together, the results of this study identify the critical role of GARS in the pathogenesis of psoriasis and suggest that blocking GARS may be a therapeutic approach for alleviating psoriasis.

Biology of melanocytes in mammals.

Melanocytes, which originate from the neuroectoderm, are specialized cells responsible for producing pigments and possessing a dendritic morphology. These cells migrate to the epidermis and follicles, contributing to skin and hair pigmentation during embryonic development. The remarkable self-renewal capacity of melanocytes enables them to effectively restore hair and skin pigmentation. The synthesis of melanin to safeguard the skin against damage caused by ultraviolet radiation, as well as the enigmatic immune function of melanocytes, demonstrate their indispensable contributions to maintaining cutaneous homeostasis. The regulation of cutaneous pigmentation involves an intricate network influenced by intrinsic cellular signals within melanocytes and extracellular cues. Therefore, this paper provides a comprehensive review of the role of melanocytes in skin biology. This in-depth analysis could open novel avenues for research aimed at the prevention and treatment of skin disorders.

Epidermal keratinocyte-specific STAT3 deficiency aggravated atopic dermatitis-like skin inflammation in mice through TSLP upregulation.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.

Mupirocin blocks imiquimod-induced psoriasis-like skin lesion by inhibiting epidermal isoleucyl-tRNA synthetase.

BACKGROUND: The Isoleucyl-tRNA synthetase (IARS) catalyzes isoleucine to the corresponding tRNA, maintaining the accuracy of gene translation. Its role in psoriasis has been not investigated so far. In this study, we aimed to investigate the mechanisms underlying the efficacy of IARS inhibitor, mupirocin, treatment for psoriasis. METHODS: The expression of IARS was determined by immunofluorescence, Western blot and qRT-PCR in normal healthy control- and psoriatic human skin. An imiquimod (IMQ) -induced psoriasis-like skin disease model was used to study the phenotypes changed by an IARS inhibitor, mupirocin (MUP). Endotypes were analyzed by RNA-seq, R&D Luminex multi-factor technique, ELISA, immunofluorescence and flow cytometry. Additionally, the effect of MUP on epidermal keratinocytes (KCs) were conducted in-vitro in primary cultured human KCs. RESULTS: We found the expression of IARS was higher in psoriatic skin than in healthy controls. In IMQ-induced psoriasis-like C57BL/6 J mouse model, MUP reversed IMQ-induced keratinocytes proliferation, expression of inflammatory cytokines and infiltration of immune cells. Furthermore, in cultured human keratinocytes, MUP inhibited proliferation, but promoted apoptosis, which may be related with STAT3 signaling pathway. CONCLUSION: Our finding of blocking the infiltration of immune cells by inhibiting the formation of IARS, could be one mechanism to explain the effect of MUP in the treatment of psoriasis. Developing strategies targeting suppression IARS should open new perspectives for the treatment of psoriasis. Video Abstract.

Cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes.

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

OAS1, OAS2, and OAS3 Contribute to Epidermal Keratinocyte Proliferation by Regulating Cell Cycle and Augmenting IFN-1‒Induced Jak1‒Signal Transducer and Activator of Transcription 1 Phosphorylation in Psoriasis.

Psoriasis is a systemic immune‒mediated inflammatory disease characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes. Recent studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis, but the underlying molecular mechanisms remain unclear. The 2'-5'-oligoadenylate synthetases (OASs), namely, OAS1, OAS2, OAS3, and OASL, are a family of IFN-induced enzymes with multiple antiviral activities, but their role in psoriasis is unknown. In this study, we identified the overexpression of OAS1, OAS2, and OAS3 in human lesional psoriatic skin and serum and found that their expression was downregulated by biologics. Moreover, OASs were highly expressed in epidermal keratinocytes, epidermal dendritic cells, epidermal CD3+ T cells, dermal antigen-presenting cells, and dermal T cells from the psoriatic epidermis and dermis, as determined by flow cytometry. In addition, OASs were upregulated by poly(I:C), poly(dA:dT), and IFN-1s but downregulated by Jak inhibitors in normal human epidermal keratinocytes. Furthermore, silencing of OASs inhibited the phosphorylation of Jak1 and signal transducer and activator of transcription 1. Knockdown of OASs suppressed keratinocyte proliferation by inhibiting cell cycle progression. Thus, OASs may be therapeutic biomarkers in psoriasis.

Enhancement of T Follicular Helper Cell-Mediated Humoral Immunity Reponses During Development of Experimental Autoimmune Myasthenia Gravis.

Myasthenia gravis (MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper (Tfh) cells have been implicated in many autoimmune diseases. However, whether and how Tfh cells are involved in MG remain unclear. Here, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha (AChRα) subunit (R-AChR97-116)-induced experimental autoimmune myasthenia gravis (EAMG). This model presented mild body-weight loss 10 days after the first immunization (representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization (representing the late stage of disease). AChR-specific pre-Tfh cells and mature Tfh cells were detected in these two stages, respectively. In co-cultures of Tfh cells and B cells, the number of IgG2b-secreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived Tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4+/Bcl-6+ T cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, we hypothesize that an AChR-specific Tfh cell-mediated humoral immune response contributes to the development of EAMG.

Cerebral microbleeds - prevalence, distribution and risk factors in northeast population without preceding large-area stroke.

BACKGROUND: Cerebral microbleeds (CMBs) occur frequently in patients suspected of cerebrovascular disease and they are the principle radiographic findings in patients with sub-clinical neurological impairment. The objective of this study was to assess the prevalence, distribution, severity and associated clinical features of CMBs in a prospective hospital patient based cohort undergoing brain MRI for suspected cerebrovascular disease, excluding cases with known intracranial hemorrhage or prior large-area stroke. METHODS: The study population consisted of 447 patients who were evaluated with T2*-gradient echo sequences to detect the CMBs lesion number, location, and their association with white matter hyperintensities and clinical parameters, including blood pressure. RESULTS: CMB lesions were presented in 95 of the 447 patients (21.3%). The distribution of CMBs was 43.95% cortical, 19.77% thalamic, 14.41% in the brainstem, 11.58% cerebellar, 6.21% periventricular white matter, 5.64% involving the basal ganglia regions, and 0.28% involving the hippocampus. There was a statistically significant association between the presence of CMBs and advancing age (adjusted OR 2.082, P < 0.01), the severity of hypertension (adjusted OR 2.208, P < 0.01). Also there was a statistically significant (P < 0.01) correlation between the presence of CMBs and the severity of hypertension and white matter lesions. CONCLUSIONS: CMBs occur frequently in patients with no prior large-area stroke who were referred for brain MRI for suspected cerebrovascular disease. The severity of CMBs correlates with the severity of hypertension and the presence of cerebral white matter changes detected by MRI.