Dysregulation of Connexin Expression Plays a Pivotal Role in Psoriasis

Background: Psoriasis, a chronic inflammatory disease affecting 2–3% of the population, is characterised by epidermal hyperplasia, a sustained pro-inflammatory immune response and is primarily a T-cell driven disease. Previous work determined that Connexin26 is upregulated in psoriatic tissue. This study extends these findings. Methods: Biopsies spanning psoriatic plaque (PP) and non-involved tissue (PN) were compared to normal controls (NN). RNA was isolated and subject to real-time PCR to determine gene expression profiles, including GJB2/CX26, GJB6/CX30 and GJA1/CX43. Protein expression was assessed by immunohistochemistry. Keratinocytes and fibroblasts were isolated and used in 3D organotypic models. The pro-inflammatory status of fibroblasts and 3D cultures was assessed via ELISA and RnD cytokine arrays in the presence or absence of the connexin channel blocker Gap27. Results: Connexin26 expression is dramatically enhanced at both transcriptional and translational level in PP and PN tissue compared to NN (>100x). In contrast, CX43 gene expression is not affected, but the protein is post-translationally modified and accumulates in psoriatic tissue. Fibroblasts isolated from psoriatic patients had a higher inflammatory index than normal fibroblasts and drove normal keratinocytes to adopt a “psoriatic phenotype” in a 3D-organotypic model. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap27. Conclusion: dysregulation of the connexin26:43 expression profile in psoriatic tissue contributes to an imbalance of cellular events. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit.

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Identification and Validation of the Signatures of Infiltrating Immune Cells in the Eutopic Endometrium Endometria of Women With Endometriosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.671201 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiang-Guang Wu ◽

Jin-Jiao Chen ◽

Hui-Ling Zhou ◽

Yu Wu ◽

Fei Lin ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Nk Cells ◽

Immune Cells ◽

Expression Profiles ◽

Embryo Implantation ◽

Gene Expression Profiles ◽

Signalling Pathway ◽

Clinical Samples ◽

Normal Controls

Endometriosis is an oestrogen-dependent chronic inflammatory process with primary symptoms including dysmenorrhea, chronic pelvic pain, and infertility. The immune environment of the endometrium is essential for successful embryo implantation and ongoing pregnancy. In this study, we assessed the composition, density, and distribution of infiltrating immune cells in the endometria of women with endometriosis. Gene expression profiles of endometrial samples were downloaded from the Gene Expression Omnibus (GEO) database. We found that the TNF signalling pathway, the IL-17 signalling pathway, and the MAPK signalling pathway were significantly enriched in the eutopic endometria of women with endometriosis. The fractions and proportion of infiltrating immune cells were estimated by the CIBERSORT, MCP-counter, and ImmuCellAI methods. We found that the proportions of CD8+ T cells, activated NK cells, and follicular helper T cells were significantly higher in the endometria of women with endometriosis than in the endometria of normal controls, while the proportions of M2 macrophages and resting mast cells were significantly lower in the eutopic endometria. In GSE120103 (n = 36), we found that elevated CD8+ T cells in endometriosis increased the risk of infertility (P = 0.0019). The area under the receiver operating characteristic (ROC) curve (AUC) of CD8+ T cells to distinguish fertile and infertile endometriosis was 0.914. In clinical samples (n = 40), we found that the proportions of CD8+ T cells and CD56+ NK cells were significantly higher in the eutopic endometria of women with endometriosis than in the endometria of normal controls, while the proportion of CD163+ macrophages were lower in the eutopic endometria. The AUCs of CD8+ T cells and CD163+ macrophages were 0.727 and 0.833, respectively, which indicated that CD8 and CD163 were potential diagnostic markers for endometriosis. In conclusion, our results demonstrated that increased CD8+ T cells and CD56+ NK cells and decreased CD163+ macrophages within the eutopic endometria of women with endometriosis reveal a proinflammatory feature in the endometrial immune environment and that elevated CD8+ T cells increase the risk of infertility in women with the disease.

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528 Sexual dimorphism in myeloid-derived suppressor cells promote GBM progression in females via IL-1b

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0528 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A564-A564

Author(s):

Defne Bayik ◽

Yadi Zhou ◽

Chihyun Park ◽

Chngjin Hong ◽

Danielle Silver ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Suppressor Cells ◽

Primary Source ◽

Neutralizing Antibody ◽

Therapeutic Benefit ◽

Activation Markers ◽

Accumulation Pattern

BackgroundA potently immunosuppressive tumor microenvironment facilitates progression of glioblastoma (GBM). Immunotherapies have had variable success in improving the outcome of GBM patients, suggesting that there is a need to gain insight into the mechanisms of immunosuppression. Our findings indicated that proliferating monocytic MDSCs (mMDSCs) accumulate in tumors of male mice and patients, while female tumor-bearing mice had an increase in circulating granulocytic MDSC (gMDSC) frequency, and a high gMDSC gene signature correlated with worse outcome of female patients.MethodsTo investigate the basis and prognostic value of sex differences in MDSC profile, we analyzed the role of sex hormones, determined gene expression signatures of MDSCs and preclinically tested the therapeutic benefit of candidate drugs predicted to be effective against individual MDSC subsets.ResultsIn line with the differential MDSC accumulation pattern, targeting the systemic gMDSCs with the anti-Ly6G neutralizing antibody extended the lifespan of female mice without affecting males. These differences were not driven by sex steroids, as castration or ovariectomy failed to alter MDSC subset accumulation patterns in GBM-bearing mice. Drug-prediction algorithms using the differential MDSC gene expression profiles predicted IL-1 inhibitors are effective against gMDSCs. Correspondingly, IL-1β was highly expressed in female but not male gMDSCs. Single-cell sequencing revealed that circulating but not tumor-infiltrating gMDSCs were the primary source of IL-1β and that its neutralization provided a female-specific survival advantage by reducing circulating gMDSCs. This was accompanied by declines in tumor infiltration of microglia, microglia activation status and tumor cell proliferation. In vitro, IL-1β inhibition reduced viability and expression of activation markers by primary microglia.ConclusionsThese findings highlight a novel peripheral gMDSC-microglia IL-1β mediated communication axis in female GBM and indicate expression differences in MDSC subsets can be leveraged for improved immunotherapy efficacy in a sex-specific, precision medicine strategy.

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