ABSTRACT
CIITA, a member of NOD-like receptor (NLR) family, is the major MHC II trans-activator and mediator of Th1 immunity, but its function and interaction with NLRP3 have been little studied. We found activation of NLRP3 inflammasome, increased expression of CIITA, CBP, pSTAT1, STAT1, MHC II, IFN-γ and IFN-γ-inducible chemokines (CCL1 and CXCL8), and colocalisation of NLRP3 with CIITA in Malassezia folliculitis lesions, Malassezia globosa-infected HaCaT cells and mouse skin. CoIP with anti-CIITA or anti-NLRP3 antibody pulled down NLRP3 or both CIITA and ASC. NLRP3 silencing or knockout caused CIITA downexpression and their colocalisation disappearance in HaCaT cells and mouse skin of Nlrp3-/- mice, while CIITA knockdown had no effect on NLRP3, ASC, IL-1ß and IL-18 expression. NLRP3 inflammasome inhibitors and knockdown significantly suppressed IFN-γ, CCL1, CXCL8 and CXCL10 levels in M. globosa-infected HaCaT cells. CCL1 and CXCL8 expression was elevated in Malassezia folliculitis lesions and reduced in Nlrp3-/- mice. These results demonstrate that M. globosa can activate NLRP3 inflammasome, CIITA/MHC II signalling and IFN-γ-inducible chemokines in human keratinocytes and mouse skin. NLRP3 may regulate CIITA by their binding and trigger Th1 immunity by secreting CCL1 and CXCL8/IL-8, contributing to the pathogenesis of Malassezia-associated skin diseases.
Subject(s)
Chemokines, C , Folliculitis , Malassezia , Humans , Mice , Animals , Interferon-gamma , Interferons , Histocompatibility Antigens Class II/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Inflammasomes , Promoter Regions, Genetic , Trans-Activators/genetics , Trans-Activators/metabolism , Chemokines/genetics , KeratinocytesABSTRACT
Ferredoxin reductase (FDXR), a mitochondrial membrane-associated flavoprotein, is essential for electron transfer and modulates p53-dependent apoptosis in cancer cells.FDXR may be implicated in epidermal and sebocytic differentiation, but its explicit function in sebocytes remains to be elucidated. In the present study, immunohistochemistry revealed that FDXR expression was increased in sebaceous cells of acne lesions. FDXR, PPARγ, LXRα/ß, SREBP1 and Sox9 expression was incremental during sebocyte differentiation. FDXR overexpression induced by Ad-GFP-FDXR infection enhanced differentiation, reactive oxygen species (ROS), lipogenesis and PPARγ expression, and consequnently inhibited proliferation in SZ95 sebocytes. Flow cytometry showed that FDXR overexpression induced significant blockade of G2/M phase but had no effect on sub-G1 (apoptotic) sebocytes. Insulin-like growth factor-1 (IGF-1)-induced FDXR and PPARγ expression and lipogenesis were abolished by pretreatment with PI3K inhibitor LY294002. These results suggest that FDXR overexpression might promote differentiation and lipogenesis via ROS production and suppress proliferation via G2/S blockade in SZ95 sebocytes. IGF-1 could facilitate differentiation and lipogenesis through PI3K/Akt/FDXR pathway. FDXR could serve as a potential marker of advanced sebaceous differentiation, and its overexpression may be involved in the development of acne lesions.
Subject(s)
Apoptosis/drug effects , Cell Cycle/drug effects , Cell Differentiation/drug effects , Ferredoxins/pharmacology , Lipogenesis/drug effects , Cell Respiration/drug effects , Epithelial Cells/drug effects , HumansABSTRACT
We describe a 17-year-old man who developed penile annular and scrotal eczematoid syphilids with penile chancre redux. Dermoscopy showed linear-irregular and hairpin vessels with white scales in annular lesions. Histopathology displayed psoriasiform hyperplasia with perivascular lymphoplasmacytic dermal infiltrate. Rapid plasma reagin and Treponema pallidumparticle agglutination assays were positive. The lesions disappeared after intramuscular benzathine penicillin.
Subject(s)
Chancre/pathology , Syphilis, Cutaneous/pathology , Adolescent , Anti-Bacterial Agents/therapeutic use , Chancre/diagnostic imaging , Chancre/drug therapy , Dermoscopy , Humans , Male , Penicillin G Benzathine/therapeutic use , Penis/diagnostic imaging , Penis/pathology , Scrotum/diagnostic imaging , Scrotum/pathology , Syphilis, Cutaneous/diagnostic imaging , Syphilis, Cutaneous/drug therapy , Treatment OutcomeABSTRACT
Immunophenotyping of inflammatory dermal infiltrates in Malassezia folliculitis (MF) and pityriasis versicolor (PV) lesions is less reported. Immunohistochemistry was performed on 21 MF lesions, 10 PV lesions, and 10 control skin. CD3+, CD4+, CD8+, CD20+, CD68+, and CD117+ cells were increased in MF compared with PV and normal skin (P < 0.01-0.05), while CD3+, CD4+, and CD20+ cells were higher in PV than in normal skin (P < 0.05). Dermal CD1a+ cells were higher only in PV (P < 0.05). Although both cellular and humoral immune responses are involved in pathogenesis of MF and PV, their difference may contribute to clinicopathological discrepancy between two disorders. LAY SUMMARY: Malassezia folliculitis and pityriasis versicolor are common Malassezia-induced superficial mycoses. Their clinicopathological discrepancy may be due to the difference of cellular and humoral immune responses.
Subject(s)
Dermatomycoses , Folliculitis , Malassezia , Tinea Versicolor , Dermatomycoses/immunology , Folliculitis/immunology , Humans , Immunophenotyping , Tinea Versicolor/immunologySubject(s)
Dizziness , Headache , Muscle Weakness , Humans , Dizziness/etiology , Headache/etiology , Muscle Weakness/etiology , Male , Magnetic Resonance Imaging , Leg/pathology , Brain/diagnostic imaging , Brain/pathology , Histocytochemistry , Microscopy , Female , Middle AgedABSTRACT
Forkhead box-O1 (FoxO1) is a key nutrient- and growth factor-dependent regulator of metabolism, but its functional role in human primary keratinocytes (HPKs) is less known. To investigate the role of FoxO1 in HPKs and effect of insulin-like growth factor 1 (IGF-1) and isotretinoin on FoxO1 expression, HPKs were treated with 1.2 mmol/L calcium chloride, 1-20 ng/mL IGF-1 and 0.1-10 µmol/L isotretinoin. Recombinant adenovirus expressing FoxO1 or FKHR shRNA lentivirus transfection was introduced to upregulate or silence FoxO1 expression. Epidermal FoxO1 immunostaining was lower in acne lesion than in normal skin. FoxO1 overexpression induced involucrin expression, G2/M arrest and apoptosis but suppressed proliferation, while FoxO1 silencing decreased involucrin expression but increased proliferation, S phase and viable cells in HPKs. IGF-1 downregulated FoxO1 and involucrin but upregulated p-Akt expression in HPKs, which was blocked by pretreatment with LY294002. Isotretinoin enhanced FoxO1, p53 and p21 but inhibited p-FoxO1 and involucrin expression in HPKs. These results demonstrate that FoxO1 promotes differentiation and apoptosis in HPKs. IGF-1 may reduce keratinocyte differentiation through PI3K/Akt/FoxO1 pathway, while isotretinoin can reinforce FoxO1 expression. FoxO1 may be involved in acne pathogenesis and could serve as a potential therapeutic target.
Subject(s)
Apoptosis/genetics , Cell Cycle Checkpoints/genetics , Cell Differentiation/genetics , Forkhead Box Protein O1/genetics , Keratinocytes/physiology , Acne Vulgaris/metabolism , Cell Differentiation/drug effects , Cell Proliferation/genetics , Cell Survival/genetics , Cells, Cultured , Chromones/pharmacology , Dermatologic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Forkhead Box Protein O1/metabolism , Gene Expression/drug effects , Gene Silencing , Humans , Insulin-Like Growth Factor I/pharmacology , Isotretinoin/pharmacology , Morpholines/pharmacology , Phosphorylation , Primary Cell Culture , Protein Precursors/genetics , Protein Precursors/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Transfection , Tumor Suppressor Protein p53/metabolism , Up-RegulationABSTRACT
Becker's naevus is androgen-dependent. The aim of this study was to investigate whether oestrogen and progesterone receptors are involved in this disorder. Immunohistochemistry showed that epidermal expression of androgen receptors, oestrogen receptors (α, ß) and progesterone receptors was higher in skin lesions of Becker's naevus than in perilesional and control skin. Androgen receptor overexpression was observed in pilosebaceous glands, while oestrogen and progesterone receptor overexpression was seen in hair follicles, but not in sebaceous glands in skin lesions compared with perilesional skin. Reverse tran-scription PCR and Western blot revealed that levels of androgen, oestrogen and progesterone receptors were generally upregulated in skin lesions compared with perilesional and control skin, and their expression was usually higher in perilesional than in control skin. These results suggest that simultaneous overexpression of androgen, oestrogen and progesterone receptors might be implicated in the pathogenesis of Becker's naevus.
Subject(s)
Estrogen Receptor alpha/analysis , Estrogen Receptor beta/analysis , Nevus/chemistry , Receptors, Androgen/analysis , Receptors, Progesterone/analysis , Skin Neoplasms/chemistry , Adolescent , Adult , Blotting, Western , Child , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Female , Humans , Immunohistochemistry , Male , Nevus/genetics , Nevus/pathology , Receptors, Androgen/genetics , Receptors, Progesterone/genetics , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Up-Regulation , Young AdultABSTRACT
The activation of NLRP3, NLRC4 and AIM2 inflammasomes is pivotal for innate immunity against some pathogenic fungi, but their role in the pathogenesis of Malassezia folliculitis (MF) remains unclear. The objective of the study was to determine the expression of 4 canonical inflammasomes (NLRP1, NLRP3, NLRC4 and AIM2) and their priming-associated molecules (TLR2, TLR4, Dectin-1, Dectin-2 and NFκB) in MF lesion. Expression of NLRP1, NLRP3, NLRC4, AIM2, caspase-1, IL-1ß, TLR2, TLR4, Dectin-1, Dectin-2 and NFκB was detected by immunohistochemistry in skin lesion of 23 MF patients and normal skin of 12 healthy subjects. Furthermore, NLRP1, NLRP3, NLRC4, AIM2, caspase-1 and IL-1ß mRNA was measured by quantitative real-time PCR (qRT-PCR) in 12 MF cases and 10 controls. Immunohistochemical analysis revealed that NLRP3, NLRC4, AIM2, Casp-1, IL-1ß, TLR2, TLR4, Dectin-1, Dectin-2 and NFκB expression was up-regulated in the epidermis and dermal inflammatory cells of MF lesion compared with control skin (P < .01-.05), but NLRP1 expression was not different between both groups (P > .05). qRT-PCR showed that levels of NLRP3, Casp-1 and IL-1ß mRNA were significantly increased (P < .01-.05), whereas those of NLRP1, NLRC4 and AIM2 mRNA were slightly augmented compared to control skin (P > .05). Our observation suggests that simultaneous activation of NLRP3, NLRC4 and AIM2 inflammasomes may play an important role in the pathogenesis of MF.
Subject(s)
Dermatomycoses/pathology , Folliculitis/pathology , Immunity, Innate , Immunologic Factors/biosynthesis , Inflammasomes/biosynthesis , Malassezia/growth & development , Adolescent , Adult , Humans , Immunohistochemistry , Male , Real-Time Polymerase Chain Reaction , Young AdultSubject(s)
Chromoblastomycosis , Male , Humans , Aged , Chromoblastomycosis/diagnosis , Chromoblastomycosis/drug therapy , CladosporiumABSTRACT
The symptoms of vaginal candidiasis exacerbate in the second half of the menstrual cycle in premenopausal women when the serum estradiol level is elevated. Estradiol has been shown to inhibit Th17 differentiation and production of antifungal IL-17 cytokines. However, little is known about the mechanisms. In the present study, we used mouse splenocytes and found that estradiol inhibited Th17 differentiation through downregulation of Rorγt mRNA and protein expression. Estradiol activated estrogen receptor (ER)α to recruit repressor of estrogen receptor activity (REA) and form the ERα/REA complex. This complex bound to three estrogen response element (ERE) half-sites on the Rorγt promoter region to suppress Rorγt expression. Estradiol induced Rea mRNA and protein expression in mouse splenocytes. Using Rea small interfering RNA to knock down Rea expression enhanced Rorγt expression and Th17 differentiation. Alternatively, histone deacetylase 1 and 2 bound to the three ERE half-sites, independent of estradiol. Histone deacetylase inhibitor MS-275 dose- and time-dependently increased Rorγt expression and subsequently enhanced Th17 differentiation. In 15 healthy premenopausal women, high serum estradiol levels are correlated with low RORγT mRNA levels and high REA mRNA levels in the vaginal lavage. These results demonstrate that estradiol upregulates REA expression and recruits REA via ERα to the EREs on the RORγT promoter region, thus inhibiting RORγT expression and Th17 differentiation. This study suggests that the estradiol/ERα/REA axis may be a feasible target in the management of recurrent vaginal candidiasis.
Subject(s)
Cell Differentiation/immunology , Estradiol/immunology , Estrogen Receptor alpha/immunology , Multiprotein Complexes/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , Repressor Proteins/immunology , Response Elements/immunology , Th17 Cells/immunology , Transcription, Genetic/immunology , Adult , Animals , Benzamides/pharmacology , Candidiasis/immunology , Candidiasis/pathology , Dose-Response Relationship, Drug , Female , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , Prohibitins , Pyridines/pharmacology , Th17 Cells/pathology , Transcription, Genetic/drug effects , Up-Regulation/drug effects , Up-Regulation/immunology , Vagina/immunology , Vagina/pathologySubject(s)
Scabies , Aged, 80 and over , Animals , Centenarians , Humans , Sarcoptes scabiei , Scabies/diagnostic imagingSubject(s)
Lice Infestations , Male , Humans , Aged, 80 and over , Lice Infestations/diagnosis , Dermoscopy , Octogenarians , Pubic BoneABSTRACT
To date, only one case of post-traumatic endophthalmitis caused by Scedosporium dehoogii has been reported, but its contamination or colonization might not be precluded due to the absence of pathogenic isolation and/or pathological examination. We report the first case to our knowledge of S. dehoogii-induced subcutaneous scedosporiosis in a psoriatic patient. A 58-year-old man with 5-year history of psoriasis vulgaris and immunosuppressant therapy developed pyrexia and multiple subcutaneous abscesses on both knees. Direct microscopy of the yellowish pus showed masses of bright green short spores. Skin biopsy revealed some branched septate hyphae within the granuloma. Two aspirated pus specimens collected at a 1-week interval produced white cottony colonies on Sabouraud dextrose agar. Bacterial cultures of one blood and two purulent samples were negative, and fungal culture of blood sample was not performed. The isolate was identified as S. dehoogii using ß-tubulin phylogeny and species-specific PCR with primer MSDE1/MSA2. Without addition of antifungal treatment, subcutaneous lesions disappeared spontaneously after immunosuppressant withdrawal and no relapse occurred during 64-month follow-up. The spontaneous recovery may result from immune reconstitution following immunosuppressant discontinuation.
Subject(s)
Dermatomycoses/diagnosis , Dermatomycoses/pathology , Psoriasis/complications , Remission, Spontaneous , Scedosporium/isolation & purification , Humans , Male , Microbiological Techniques , Microscopy , Middle Aged , Phylogeny , Polymerase Chain Reaction , Sequence Analysis, DNA , Tubulin/geneticsABSTRACT
Trichophyton interdigitale is generally deemed as an anamorph of Arthroderma vanbreuseghemii based on internal transcribed spacer (ITS) sequencing, but recently their anamorph/teleomorph connection should be cautioned based on ß-tubulin phylogeny. We report three siblings and one consulting doctor who developed kerion and tinea corporis after contact with domestic rabbits. Seven same strains were isolated from four patients and three regions of a sick rabbit. The ITS and D1/D2 sequences of our isolate were 99 % homologous to A. Vanbreuseghemii, while ß-tubulin sequence was 100 % identical to T. interdigitale. Our isolate was identified as T. interdigitale based on maximum likelihood analysis of ß-tubulin. Random amplified polymorphic DNA revealed that the band patterns of five isolated strains and another rabbit-derived strain WCH023 were identical for OPF-03 and OPF-12. Skin lesions of all patients resolved completely for 2- to 6-week therapy of oral terbinafine and topical 1 % bifonazole or 1 % terbinafine cream. This study demonstrates that T. interdigitale of rabbit origin can cause various types of human dermatophytosis by mild scratch. Terbinafine may be the first choice for dermatophytosis caused by T. interdigitale.
Subject(s)
Tinea/diagnosis , Tinea/epidemiology , Trichophyton/isolation & purification , Zoonoses/diagnosis , Zoonoses/epidemiology , Amplified Fragment Length Polymorphism Analysis , Animals , Antifungal Agents/administration & dosage , Child , Cluster Analysis , DNA, Fungal/chemistry , DNA, Fungal/genetics , DNA, Ribosomal/chemistry , DNA, Ribosomal/genetics , DNA, Ribosomal Spacer/chemistry , DNA, Ribosomal Spacer/genetics , Female , Genotype , Humans , Imidazoles/administration & dosage , Male , Middle Aged , Naphthalenes/administration & dosage , Phylogeny , Physicians , RNA, Ribosomal/genetics , Rabbits , Sequence Analysis, DNA , Sequence Homology , Siblings , Terbinafine , Tinea/microbiology , Tinea/pathology , Treatment Outcome , Trichophyton/classification , Trichophyton/genetics , Tubulin/genetics , Zoonoses/microbiology , Zoonoses/pathologyABSTRACT
Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1ß. To elucidate the role of inflammasome components in T. gondii-infected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine IL-1ß secretion. The results revealed a significant upregulation of IL-1ß after T. gondii infection. T. gondii infection also upregulated the expression of inflammasome sensors, including NLRP1, NLRP3, NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and NAIP, in a time-dependent manner. The infection also upregulated inflammasome adaptor protein ASC and caspase-1 mRNA levels. From this study, we newly found that T. gondii infection regulates NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and neuronal apoptosis inhibitor protein (NAIP) gene expressions in THP-1 macrophages and that the role of the inflammasome-related genes may be critical for mediating the innate immune responses to T. gondii infection.