Background Nonsense mutations in filaggrin (FLG) represent a significant genetic factor in the cause of atopic dermatitis (AD). Objective It is of great importance to find drug candidates that ...upregulate FLG expression and to determine whether increased FLG expression controls the development of AD. Methods We screened a library of bioactives by using an FLG reporter assay to find candidates that promoted FLG mRNA expression using a human immortalized keratinocyte cell line (HaCaT). We studied the effect of the compound on keratinocytes using the human skin equivalent model. We examined the effect of the compound on AD-like skin inflammation in NC/Nga mice. Results JTC801 promoted FLG mRNA and protein expression in both HaCaT and normal human epidermal keratinocytes. Intriguingly, JTC801 promoted the mRNA and protein expression levels of FLG but not the mRNA levels of other makers for keratinocyte differentiation, including loricrin, keratin 10, and transglutaminase 1, in a human skin equivalent model. In addition, oral administration of JTC801 promoted the protein level of Flg and suppressed the development of AD-like skin inflammation in NC/Nga mice. Conclusion This is the first observation that the compound, which increased FLG expression in human and murine keratinocytes, attenuated the development of AD-like skin inflammation in mice. Our findings provide evidence that modulation of FLG expression can be a novel therapeutic target for AD.
Background Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of ...skin inflammation have yet to be examined. Objective Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD and the underlying mechanism of eosinophil infiltration of the skin. Methods We induced croton oil–induced ICD in eosinophil-deficient ΔdblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow–derived basophils and evaluated eosinophil migration using a chemotaxis assay. Results ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts in vitro. Conclusion Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novel concept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the development of skin inflammation.
For patients with adult T-cell leukaemia, asymptomatic carriers of HTLV-1 have been widely considered acceptable as donors in allogeneic stem-cell transplantation.1 The immune system is thought to ...have an important role in leukaemia occurrence in HTLV-1-seropositive carriers.2 The only reported case of donor-derived adult T-cell leukaemia was in 2006, in an immunosuppressed recipient of a peripheral-blood stem-cell transplant.3 No cases of donorderived adult T-cell leukaemia have been reported in immunocompetent patients. The prognosis tends to be better for these patients than for those with CNS involvement subsequent to systemic adult T-cell leukaemia.4 Only two cases of isolated CNS involvement have been reported so far.4,5 The function of CD4-positive cells was not fully analysed, so there is a possibility of some functional deficit in immune reconstitution.
Advances in neurosurgical techniques and neuroimaging resolution questions the modern-day reliability of the Simpson grade for predicting meningioma recurrence. Therefore, we evaluated the ...reliability of predictors for recurrence and outcomes in detail in patients with non-skull base meningiomas (NSBMs).
We retrospectively analyzed data from consecutive 175 NSBMs underwent surgical resection. We performed Kaplan–Meier analyses of recurrence-free survival (RFS) according to Simpson and World Health Organization (WHO) grades. Predictors of RFS and clinical deterioration were estimated by univariate and multivariate analyses. Correlation between the Simpson grade and change in Karnofsky Performance Scale scores was assessed by Fisher's exact test.
Log-rank tests revealed significant correlations of both the Simpson and WHO grades with RFS for the overall cohort, convexity, and falx/tentorium meningioma. Unlike patients undergoing Simpson grade I and II resections, RFS in patients with WHO grade I and II/III tumors differed significantly from the early postoperative stage. Multivariate analysis identified tumor size, Simpson grade, and MIB-1 labeling index as significant predictors of RFS. Clinical deterioration was more frequent among patients undergoing less aggressive resection. Tumor location was the only significant predictor of clinical deterioration.
Our findings indicate that tumor size, Simpson and WHO grades, and MIB-1 labeling index are significant predictors of NSBM recurrence. Moreover, the risk of recurrence markedly decreases within the follow-up duration of 80 months. Aggressive resection appears to minimize the risk of recurrence without evidence of clinical deterioration. Follow-up schedules should be based on the WHO grade and extent of resection.
•Significant correlations were observed between Simpson grade and RFS for NSBMs.•Significant correlations were observed between the WHO grade and RFS for NSBMs.•RFS rates gradually decreased within 80 months, reaching a plateau thereafter.•Aggressive surgery minimizes the recurrence risk without evidence of poor outcome.•Follow-up schedules should be based on the WHO grade and extent of resection.
Neutrophilic folliculitis is an inflammatory condition of hair follicles. In some neutrophilic folliculitis, such as in patients with acne and hidradenitis suppurativa, follicular hyperkeratosis is ...also observed. Neutrophilic folliculitis is often induced and/or exacerbated by a high-fat diet (HFD). However, the molecular mechanisms by which an HFD affects neutrophilic folliculitis are not fully understood.
Our aim was to elucidate how an HFD promotes the development of neutrophilic folliculitis.
Mice were fed an HFD, and their skin was subjected to histologic, RNA sequencing, and imaging mass spectrometry analyses. To examine the effect of an HFD on neutrophil accumulation around the hair follicles, phorbol 12–myristate 13–acetate (PMA) was used as an irritant to the skin.
Histologic analysis revealed follicular hyperkeratosis in the skin of HFD-fed mice. RNA sequencing analysis showed that genes related to keratinization, especially in upper hair follicular keratinocytes, were significantly upregulated in HFD-fed mice. Application of PMA to the skin induced neutrophilic folliculitis in HFD-fed mice but not in mice fed a normal diet. Accumulation of neutrophils in the skin and around hair follicles was dependent on CXCR2 signaling, and CXCL1 (a CXCR2 ligand) was produced mainly by hair follicular keratinocytes. Imaging mass spectrometry analysis revealed an increase in fatty acids in the skin of HFD-fed mice. Application of these fatty acids to the skin induced follicular hyperkeratosis and caused PMA-induced neutrophilic folliculitis even in mice fed a normal diet.
An HFD can facilitate the development of neutrophilic folliculitis with the induction of hyperkeratosis of hair follicles and increased neutrophil infiltration around the hair follicles via CXCR2 signaling.
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