ABSTRACT
Cutaneous drug reactions (CDRs) are common drug-induced allergic reactions that cause severe consequences in HIV/AIDS patients. The CCL17/CCR4 axis is involved in the immune mechanism of allergic diseases, but its role in the CDRs has not been determined. Here, we aimed to determine the role of the CCL17/CCR4 axis and the underlying mechanism involved in CDRs. In this study, the serum cytokine levels in patients with CDR and healthy controls were measured. The CCL17-triggered allergic profile was screened via a PCR array. Apoptosis of keratinocytes cocultured with CCL17-stimulated Th2 cells was analyzed by flow cytometry. An NVP-induced rat CDR model was established, and dynamic inflammatory factor levels and Th2 cells in the peripheral blood of the rats were measured. Rat skin lesions and signaling pathways in Th2 cells were also analyzed. We showed that the serum CCL17 level was significantly upregulated in CDR patients (P = 0.0077), and the Th2 cell subgroup was also significantly elevated in the CDR rats. The CCL17/CCR4 axis induces Th2 cells to release IL-4 and IL-13 via the ERK/STAT3 pathway. The CCR4 antagonist compound 47 can alleviate rash symptoms resulting from NVP-induced drug eruption, Th2 cell subgroup, IL-4, and IL-13 and inhibit keratinocyte apoptosis. Taken together, these findings indicate that the CCL17/CCR4 axis mediates CDR via the ERK/STAT3 pathway in Th2 cells and type 2 cytokine-induced keratinocyte apoptosis.
Subject(s)
Interleukin-13 , Th2 Cells , Humans , Rats , Animals , Interleukin-13/metabolism , Interleukin-4/metabolism , Cytokines/metabolism , Signal Transduction , Receptors, CCR4/metabolism , Chemokine CCL17/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
Leprosy and psoriasis rarely coexist, the specific molecular mechanisms underlying their mutual exclusion have not been extensively investigated. This study aimed to reveal the underlying mechanism responsible for the mutual exclusion between psoriasis and leprosy. We obtained leprosy and psoriasis data from ArrayExpress and GEO database. Differential expression analysis was conducted separately on the leprosy and psoriasis using DEseq2. Differentially expressed genes (DEGs) with opposite expression patterns in psoriasis and leprosy were identified, which could potentially involve in their mutual exclusion. Enrichment analysis was performed on these candidate mutually exclusive genes, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The expression of these hub genes was further validated in an external dataset to obtain the critical mutually exclusive genes. Additionally, immune cell infiltration in psoriasis and leprosy was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between critical mutually exclusive genes and immune cells was also examined. Finally, the expression pattern of critical mutually exclusive genes was evaluated in a single-cell transcriptome dataset. We identified 1098 DEGs in the leprosy dataset and 3839 DEGs in the psoriasis dataset. 48 candidate mutually exclusive genes were identified by taking the intersection. Enrichment analysis revealed that these genes were involved in cholesterol metabolism pathways. Through PPI network analysis, we identified APOE, CYP27A1, FADS1, and SOAT1 as hub genes. APOE, CYP27A1, and SOAT1 were subsequently validated as critical mutually exclusive genes on both internal and external datasets. Analysis of immune cell infiltration indicated higher abundance of 16 immune cell types in psoriasis and leprosy compared to normal controls. The abundance of 6 immune cell types in psoriasis and leprosy positively correlated with the expression levels of APOE and CYP27A1. Single-cell data analysis demonstrated that critical mutually exclusive genes were predominantly expressed in Schwann cells and fibroblasts. This study identified APOE, CYP27A1, and SOAT1 as critical mutually exclusive genes. Cholesterol metabolism pathway illustrated the possible mechanism of the inverse association of psoriasis and leprosy. The findings of this study provide a basis for identifying mechanisms and therapeutic targets for psoriasis.
Subject(s)
Arthrogryposis , Leprosy , Psoriasis , Humans , Leprosy/genetics , Psoriasis/genetics , Cholesterol , Apolipoproteins E , Computational BiologyABSTRACT
Macrophage-derived inflammatory cytokines are critical for host defense against Talaromyces marneffei (T. marneffei) infection among HIV/AIDS patients, and excessive inflammatory cytokines are associated with poor outcomes of AIDS-associated talaromycosis. However, the underlying mechanisms of macrophage-caused pyroptosis and cytokine storm are poorly understood. Here, in the T. marneffei-infected mice and macrophages, we show that T. marneffei induced pyroptosis in macrophages through the NLRP3/caspase-1 pathway. The immunomodulatory drug thalidomide could promote the pyroptosis of macrophages infected T. marneffei. In T. marneffei-infected mice, the splenic macrophages underwent increasing pyroptosis as talaromycosis deteriorated. Thalidomide ameliorated inflammation of mice, while amphotericin B (AmB) in combination with thalidomide did not improve overall survival compared with AmB alone. Taken together, our findings suggest that thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in T. marneffei infection.
Subject(s)
Talaromyces , Thalidomide , Animals , Mice , Thalidomide/pharmacology , Thalidomide/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Caspase 1/metabolism , Pyroptosis , Macrophages/metabolism , Amphotericin B , Cytokines/metabolismABSTRACT
Talaromycosis is a fatal mycosis caused by the thermally dimorphic fungus Talaromyces marneffei (T. marneffei). The pathogenic mechanisms of talaromycosis are still poorly understood. This work combined metabolomics, transcriptomics, and verification experiments in vivo and in vitro to detect metabolic proï¬les and differentially expressed genes (DEGs) in T. marneffei infected and uninfected macrophages to explore possible pathogenesis and underlying mechanisms. A total of 256 differential metabolites (117 up-regulated and 148 down-regulated) and 1320 DEGs (1286 up-regulated and 34 down-regulated) were identified between the two groups. Integrative metabolomics and transcriptomics analysis showed sphingolipid signaling pathway is the most inï¬uential. Veriï¬cation experiments showed that compared with the control group, the production of sphingosine-1-phosphate (S1P) and the expression of the S1PR1, S1PR2, phosphor-PI3K, and phosphor-Akt genes involved in the sphingolipid signaling pathway have signiï¬cantly increased in the T. marneffei infection group (p < 0.05). T. marneffei activates the S1PR2/PI3K/Akt pathways in J774A.1 macrophage, regulation of the S1P singling might serve as a promising therapeutic strategy for talaromycosis.
Subject(s)
Proto-Oncogene Proteins c-akt , Talaromyces , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Transcriptome , Macrophages/microbiology , Metabolomics , Sphingolipids/metabolism , Talaromyces/geneticsABSTRACT
BACKGROUND: HIV/AIDS patients are susceptible to various infectious and inflammatory dermatoses. No systemic work has been done on HIV/AIDS patients with immune-mediated photodermatoses in China. Here, we aim to determine the clinical features of immune-mediated photodermatoses in HIV/AIDS patients. METHODS: A retrospective analysis of HIV/AIDS patients with immune-mediated photodermatoses was carried out with demographic data, clinical characteristics, laboratory data, and follow-up data at the First Affiliated Hospital of Kunming Medical University between 2012 and 2019. The data were subjected to statistical analysis. RESULTS: A total of 39 HIV/AIDS patients with immune-mediated photodermatoses were enrolled, including 22 cases of polymorphic light eruption (PLE), 16 cases of chronic actinic dermatitis (CAD), and one actinic reticuloid. The CD4 count at the visit of the HIV-positive CAD group was lower than the PLE group (p = .049). The HIV-positive CAD group was more sensitive toward UVB than the PLE group (p = .020) and had a lower MED-UVB value (p = .044). There was no significant difference in UV tests among different categories of skin types. CONCLUSION: Immune-mediated photodermatoses are a manifestation of the advanced symptom of HIV infection, and sometimes also the presenting feature of HIV infection. Compared with HIV-positive PLE patients, CAD patients showed higher sensitivity to UVB radiation and had a lower MED-UVB value. The primary treatment for immune-mediated photodermatoses in HIV/AIDS patients is HAART and sun avoidance.
Subject(s)
Acquired Immunodeficiency Syndrome , Dermatitis, Contact , HIV Infections , Photosensitivity Disorders , Humans , Retrospective Studies , HIV , Photosensitivity Disorders/diagnosisABSTRACT
[This corrects the article DOI: 10.3389/fimmu.2022.971071.].
ABSTRACT
Background: Psoriasis is a common inflammatory skin disease that has a great impact on patients' physical and mental health. However, the causes and underlying molecular mechanisms of psoriasis are still largely unknown. Methods: The expression profiles of genes from psoriatic lesion samples and skin samples from healthy controls were integrated via the sva software package, and differentially expressed genes (DEGs) between psoriasis and healthy skin were screened by the limma package. Furthermore, GO and KEGG pathway enrichments for the DEGs were performed using the Clusterprofiler package. Protein-protein interaction (PPI) networks for the DEGs were then constructed to identify hub genes. scGESA analysis was performed on a single-cell RNA sequencing dataset via irGSEA. In order to find the cytokines correlated with the hub genes expression, single cell weighted gene co-expression network analyses (scWGCNA) were utilized to build a gene co-expression network. Furthermore, the featured genes of psoriasis found in suprabasal keratinocytes were intersected with hub genes. We then analyzed the expression of the intersection genes and cytokines in the integrated dataset. After that, we used other datasets to reveal the changes in the intersection genes' expression levels during biological therapy. The relationship between intersection genes and PASI scores was also explored. Results: We identified 148 DEGs between psoriatic and healthy samples. GO and KEGG pathway enrichment analysis suggested that DEGs are mainly involved in the defense response to other organisms. The PPI network showed that 11 antiviral proteins (AVPs) were hub genes. scGSEA analysis in the single-cell transcriptome dataset showed that those hub genes are highly expressed in keratinocytes, especially in suprabasal keratinocytes. ISG15, MX1, IFI44L, and IFI27 were the characteristic genes of psoriasis in suprabasal keratinocytes. scWGCNA showed that three cytokines-IL36G, MIF, and IL17RA-were co-expressed in the turquoise module. Only interleukin-36 gamma (IL36G) was positively correlated with AVPs in the integrated dataset. IL36G and AVPs were found co-expressed in a substantial number of suprabasal keratinocytes. Furthermore, we found that the expression levels of IL36G and the 4 AVPs showed positive correlation with PASI score in patients with psoriasis, and that these levels decreased significantly during treatment with biological therapies, but not with methotrexate. Conclusion: IL36G and antiviral proteins may be closely related with the pathogenesis of psoriasis, and they may represent new candidate molecular markers for the occurrence and severity of psoriasis.
Subject(s)
Gene Expression Profiling , Interleukin-1 , Psoriasis , Antiviral Agents , Computational Biology , Cytokines/genetics , Humans , Interleukin-1/genetics , Interleukins/genetics , Methotrexate , Psoriasis/geneticsABSTRACT
INTRODUCTION: Atopic dermatitis (AD) is one of the most common skin diseases, and it may be associated with skin cancer risk. However, there is a controversy pertaining to whether it implies a greater or decreased risk of skin cancers. We aimed to study the relationship between AD and skin cancer risk. METHODS: PubMed and Embase databases from their inception to 4 August 2021 were systematically searched. RESULTS: We evaluated 16 studies involving a total of 9,638,093 participants examining the contribution of AD to skin cancers. Random-effects model was applied to estimate the overall effect sizes. The pooled analysis of 16 studies indicated that AD was significantly associated with an overall increased risk of skin cancer. Subgroup pooled analyses showed that AD was statistically associated with an increased risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). With regard to cohort study, AD was statistically associated with an increased risk of nonmelanoma skin cancer (NMSC), BCC, and SCC, but not melanoma risk. Sensitivity analysis revealed that excluding each study in turn did not alter the overall combined results. No publication bias existed among the studies. CONCLUSION: It can be concluded that AD is associated with risk of skin cancers; however, this association still needs to be verified in well-designed, worldwide trials (especially prospective, non-Western studies). The mechanism of AD leading to skin cancer is not clear, and further research is needed to explore the possibility of a potential pathogenesis.
ABSTRACT
Old-World leaf-nosed bats (Hipposideridae) are echolocating bats with peculiar emission-side dynamics where beamforming baffles ("noseleaves") that surround the points of ultrasound emission (nostrils) change shape while diffracting the outgoing biosonar pulses. While prior work with numerical and robotic models has suggested that these noseleaf deformations could have an impact on the output characteristics of the bat's biosonar system, testing the hypothesis that this is the case in bats remains a critical step to be taken. The work presented here has tested the hypothesis that the noseleaf dynamics in a species of hipposiderid bat (Pratt's roundleaf bat, H. pratti) leads to time-variant acoustical properties on the output side of the bats' biosonar emission system. The time-variant effects of the noseleaf motion could be detected even in the presence of other sources of variability by comparing the distribution of pulse energy over the angle at different points in time. Furthermore, a convolutional neural network was able to classify the noseleaf motion state based on microphone array recordings with 85.3% accuracy. These results hence demonstrate that these nose-emitting bats have access to a substrate for behavioral flexibility on the emission-side of their biosonar systems.
Subject(s)
Chiroptera , Echolocation , Animals , Motion , NoseABSTRACT
Bat species in the rhinolophid and hipposiderid families can deform the shapes of their noseleaves (ultrasonic emission baffles) in synchrony with emission of the biosonar pulses. Prior work has shown that these physical deformations of a diffracting baffle can add a time-variant quality to the emitted pulses. Whereas conventional sonar emitters can be characterized by gain values that are functions of direction (e.g. azimuth and elevation) and frequency only, the biosonar emission characteristics in these bat species is a function of direction, frequency, and time. Prior work has indicated that the unique emission time variance seen in the bats could support the encoding of additional sensory information. In the work presented here, a biomimetic noseleaf has been used to collect a densely sampled representation of a time-variant emission characteristics. This data set has been analyzed using advanced (nearest-neighbor based) estimators for information theoretic measures such as mutual information and relative entropy. The findings from this analysis suggest three hypotheses regarding the nature of these biomimetic time-variant emitter characteristics: (i) its complexity reflects all independent physical dimensions (ii) coding capacity along the time and frequency dimensions does not differ substantially, and (iii) sensory information is accumulated continuously along a time-variant pulse.
Subject(s)
Biomimetic Materials/chemistry , Sensation , Sound , Acoustics , Animals , Chiroptera/anatomy & histology , MotionABSTRACT
The ultrasonic emission of the biosonar systems of bats, such as Old World leaf-nosed bats (family Hipposideridae) and the related horseshoe bats (family Rhinolophidae), is characterized by a unique dynamics where baffle shapes ('noseleaves') deform while diffracting the outgoing wave packets. As of now, nothing comparable to this dynamics has been used in any related engineering application (e.g. sonar or radar). Prior work with simple concave baffle shapes has demonstrated the impact of the dynamics on the emission characteristics, but it has remained unclear whether this was simply due to the change in aperture size or also influenced by the geometrical shape detail. Hence, it has also remained unclear whether it would be possible to further enhance the time-variant effects reported so far through different static and dynamic geometries. To address this issue, we have created a dynamic emission baffle with biomimetic shape detail modeled after Pratt's roundleaf bats (Hipposideros pratti). The impact of the dynamic deformation of the shape on the time-variant emission characteristics was evaluated by virtue of the gradient magnitude and the entropy in the gradient orientation. The results have shown that the dynamics results in much larger gradients in signal representation, which change jointly over direction and time.