Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression

Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.

Prevalence of Acne Inversa(Hidradenitis Suppurativa)in China:A Nationwide Cross-Sectional Epidemiological Study

Objective:This study was performed to estimate the prevalence of hidradenitis suppurativa(HS)in China and describe the demographic and clinical features of HS in the Chinese population.Methods:This multicenter clinic-based cross-sectional study was conducted in dermatology clinics within 19 hospitals located in 15 cities/provinces across China from September to October 2020.The prevalence of HS was calculated as the percentage of patients with HS among all visitors at participating clinics during the 1-month study period.HS was independently diagnosed by two certified dermatologists at each site.All visitors at participating clinics were screened,and all patients with HS were invited to participate in a questionnaire survey to elucidate the demographics and clinical features of HS in the Chinese population.Results:We identified 92 patients with HS among 274,742 visitors at participating clinics.The prevalence rate was 0.03349%or 33.49 per 100,000 population(95%confidence interval,26.64–40.32),and the female:male ratio was 1.0:4.7.Conclusion:The overall prevalence of HS in China was lower than that in Western and other Asian countries with a predominance of male patients.

Diagnosis and Treatment of Acne Inversa/Hidradenitis Suppurativa in China: An Expert Consensus Statement (2021 Version)

Acne inversa/hidradenitis suppurativa is a chronic,recurrent,inflammatory skin disease that affects the pilosebaceous units,causinfollicular occlusion.The etiology and pathogenesis of acne inversa/hidradenitis suppurativa involves internal and external factors such as genetic susceptibility,inflammation and immunity,microorganisms,obesity,and smoking.acne inversa/hidradenitis suppurativa is difficult to treat,and the current aim of treatment is to control the frequency and duration of disease flares and improve the quality of life.Treatment protocols for acne inversa/hidradenitis suppurativa should be selected based on the disease severity grade.Medical treatments include antibiotics,retinoids,biologics,immunosuppressive agents,and antiandrogen agents.Adjuvant treatments include surgery and laser/light therapies.This consensus aims to further standardize the diagnosis and treatment procedures of acne inversa/hidradenitis suppurativa in China to facilitate its diagnosis and treatment.

Surgical Management of Severe Hidradenitis Suppurativa in Women: Outcome and Quality of Life Assessment

Background: Hidradenitis suppurativa (HS) or Acne inversa sometimes referred to as Verneuil’s disease, is a rare and debilitating condition arising in the intertriginous folds that bear apocrine glands (axillae, groin, perineum, pubis, ano-genital area). It has a deleterious impact on the life of affected persons who tend to be more depressive and poorly socially and sexually connected because of pain, malodor and stigmatization. Methods: We conducted a retrospective study in Henri Mondor Hospital in Créteil, France, in order to assess the effectiveness of surgery as a radical treatment and also assess the factors related to recurrence and the surgical and sexual satisfaction in women operated for severe HS of perineum and genitalia. Results: Fifty-five women were included. We got a recurrence rate of 23.6%. 66.7% of recurrence occurred after localized excision. 83% of patients were satisfied with surgery results and would undergo a revision surgery or recommend it. The factors significantly associated with recurrence were overweight (p = 0.0046), location in groin (p = 0.0040), localized excision (p = 0.02), total excision (p = 0.009), healing via secondary intention (p = 0.001) and disability due to HS (p = 0.006). Assessment of sexual response thanks to the FSFI showed an alteration of all the domains of sexual response but the composite index of 18.51 was below the threshold to diagnose pathologic sexual condition.

NCSTN Gene Silencing Inhibits the Retinoic Acid Signaling Pathway in Human Immortalized Keratinocytes

Objective:Acne inversa is a multifactorial chronic debilitating disease.Genetic factors are involved in 40%of patients,especially the nicastrin(NCSTN)gene.However,the role of the mutated NCSTN gene in the pathogenesis of acne inversa remains unclear.Retinoic acid is recommends to treat moderate to severe acne inversa,therefor we conduct this in vitro research to study the association between NCSTN gene mutation and the retinoic acid signaling pathway in human immortalized skin keratinocyte(HaCaT)cells.Methods:HaCaT cells were infected with a lentivirus-mediated short hairpin RNA(shRNA)expression plasmid specifically targeting the NCSTN gene.Real-time polymerase chain reaction(PCR)and Western blotting were used to detect the interference efficiency of NCSTN.RNA sequencing was used to detect differential genes in the NSCTN-deficient HaCaT cells.Based on bioinformatics analysis and clinical treatment data,the retinoic acid signal pathway was selected for screening.Quantitative PCR was used to verify the changes in the expressions of retinoic acid signaling pathway-related receptors and molecules in the HaCaT cell line after NCSTN silencing.The Student t test and one-way analysis of variance were used to evaluate intergroup differences.Results:Sequencing showed that the NCSTN-shRNA lentiviral recombinant expression plasmid was successfully constructed.After lentivirus infection of HaCaT cells,real-time PCR results showed significantly reduced NCSTN mRNA expression in the interference group compared with the negative control group,and the interference efficiency was 75.0%.Western blotting showed that the inhibition rate of NCSTN protein expression in the shRNA group was 71.7%.RNA sequencing revealed significant differential expression of some genes,and changes in signaling pathways.Compared with the control group,the group with the silenced NCSTN showed significantly decreased expression of retinoic acid receptors(RARα:F=23.482,RARβ:F=603.241,RXRα:F=69.689,and RARRES1:F=167.482,and all P<0.001),and peroxisome proliferator-activated receptorγ(F=8.138,P<0.01).Conclusion:Defective function of the NCSTN gene leads to an impaired retinoic acid signaling pathway in HaCaT cells,which suggests that the retinoic acid signaling pathway may play a role on the onset of acne inversa caused by NCSTN gene mutation.