The pathogenesis of inflammatory skin diseases such as psoriasis involves the release of numerous proinflammatory cytokines, including members of the IL‐1 family. Here we report overexpression of ...IL‐1α, IL‐1β, and IL‐1 receptor antagonist mRNA, associated to expression of IL‐23p19, IL‐17A, and IL‐22 in skin cells, upon topical application of the TLR7 agonist imiquimod (IMQ) in C57BL/6J mice. IMQ‐induced skin inflammation was partially reduced in mice deficient for both IL‐1α/IL‐1β or for IL‐1 receptor type 1 (IL‐1R1), but not in IL‐1α‐ or IL‐1β‐deficient mice, demonstrating the redundant activity of IL‐1α and IL‐1β for skin inflammation. NLRP3 or apoptosis‐associated Speck‐like protein containing a Caspase recruitment domain‐deficient mice had no significant reduction of skin inflammation in response to IMQ treatment, mainly due to the redundancy of IL‐1α. However, IMQ‐induced skin inflammation was abolished in the absence of MyD88, the adaptor protein shared by IL‐1R and TLR signaling pathways. These results are consistent with the TLR7 dependence of IMQ‐induced skin inflammation. Thus, IL‐1R1 contributes to the IMQ‐induced skin inflammation, and disruption of MyD88 signaling completely abrogates this response.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
A relationship between alcohol consumption and psoriasis has been reported, but it is unclear whether alcohol consumption aggravates psoriasis. Here, we studied the effect of chronic ...ethanol (EtOH) consumption in the murine model of Aldara‐induced psoriasiform dermatitis.
Methods
C57BL/6 mice received 5% EtOH in their drinking water for 10 weeks. Dermatitis was induced from weeks 9 to 10, by applying Aldara to the shaved patch of skin on the back. Inflammation was characterized by histological and transcriptomic analyses.
Results
EtOH consumption aggravated Aldara‐induced dermatitis. The scales were more severe, epidermal thickening was more pronounced, and cutaneous expression of Th17‐related cytokines was exacerbated. Control mice simply receiving EtOH displayed minimal cutaneous inflammation, characterized by epidermal infiltrates of T lymphocytes and the overexpression of IL‐17A and the Th17‐recruiting chemokine CCL20. In vitro studies showed that low concentrations of EtOH induce the expression of CCL20 by murine epidermal keratinocytes.
Conclusion
Alcohol consumption leads to subliminar skin inflammation, which is revealed by the exacerbation of Aldara‐induced experimental psoriasiform dermatitis, likely through Th17‐type minimal skin inflammation. These results favor the systematic management of alcohol consumption in psoriatic patients.
Psoriasis is a Th17‐type archetypal disease. Aggravation of psoriasis by alcohol consumption is uncertain. In the imiquimod‐induced model of psoriasis, mice fed ethanol displayed more severe dermatitis. Ethanol consumption induced epidermal infiltrates of T lymphocytes and overexpression of Th17‐type cytokines. Keratinocytes cultured with ethanol overexpressed CCL20, a Th17‐recruiting chemokine. These results support the deleterious effect of alcohol consumption in psoriasis by upregulating Th17 inflammatory process, and favor the systematic management of alcohol abuse in psoriatic patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Oncostatin M (OSM) has been reported to be overexpressed in psoriasis skin lesions and to exert proinflammatory effects in vitro on human keratinocytes. Here, we report the proinflammatory role of ...OSM in vivo in a mouse model of skin inflammation induced by intradermal injection of murine OSM‐encoding adenovirus (AdOSM) and compare with that induced by IL‐6 injection. Here, we show that OSM potently regulates the expression of genes involved in skin inflammation and epidermal differentiation in murine primary keratinocytes. In vivo, intradermal injection of AdOSM in mouse ears provoked robust skin inflammation with epidermal thickening and keratinocyte proliferation, while minimal effect was observed after AdIL‐6 injection. OSM overexpression in the skin increased the expression of the S100A8/9 antimicrobial peptides, CXCL3, CCL2, CCL5, CCL20, and Th1/Th2 cytokines, in correlation with neutrophil and macrophage infiltration. In contrast, OSM downregulated the expression of epidermal differentiation genes, such as cytokeratin‐10 or filaggrin. Collectively, these results support the proinflammatory role of OSM when it is overexpressed in the skin. However, OSM expression was not required in the murine model of psoriasis induced by topical application of imiquimod, as demonstrated by the inflammatory phenotype of OSM‐deficient mice or wild‐type mice treated with anti‐OSM antibodies.
Oncostatin M (OSM) is a cytokine locally upregulated in several skin inflammatory disorders. Here, we show that OSM exerts proinflammatory activities in vitro on mouse keratinocytes and in vivo when it is overexpressed in mouse skin. OSM induces the expression of antimicrobial peptides, chemokines, and cytokines and inhibits epidermal differentiation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with inflammation and tissue remodeling including myofibroblasts differentiation and extracellular matrix (ECM) deposition mediated by ...TGF-β1 and IL-4. Oncostatin M (OSM) is a cytokine involved in fibrotic processes in other cellular subtypes. We investigated the mechanisms of action of OSM in the fibrosis process associated with CRSwNP. The expression of IL-4, OSM and TGF-β1 was assessed by RT-qPCR. Primary human cultures of nasal-polyp-derived fibroblasts were established and stimulated by TGF-β1 and/or IL-4 and/or OSM. The expression of ECM components and αSMA was determined by RT-qPCR and Western blot. TGF-β1-Smad3 signaling was investigated by immunofluorescence. TGF-β1, IL-4 and OSM as well as αSMA were overexpressed in nasal polyps when compared to noninflammatory nasal mucosa. In TGF-β1-stimulated nasal-polyp-derived fibroblasts, ECM genes and αSMA gene and protein were overexpressed, as well as αSMA in IL-4-stimulated fibroblasts. OSM counteracted the profibrotic effect of TGF-β1 on ECM components and αSMA. TGF-β1-induced nuclear translocation of Smad3 was completely reversed by OSM. OSM counteracts the profibrotic effect of IL-4 and also TGF-β1, by inhibiting the nuclear translocation of Smad3. We suggest OSM could be an efficient tool to protect against fibrosis in CRSwNP.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Human herpesvirus 6 (HHV-6) is widely spread in the human population and has been associated with several neuroinflammatory diseases, including multiple sclerosis. To develop a small-animal model of ...HHV-6 infection, we analyzed the susceptibility of several lines of transgenic mice expressing human CD46, identified as a receptor for HHV-6. We showed that HHV-6A (GS) infection results in the expression of viral transcripts in primary brain glial cultures from CD46-expressing mice, while HHV-6B (Z29) infection was inefficient. HHV-6A DNA persisted for up to 9 months in the brain of CD46-expressing mice but not in the nontransgenic littermates, whereas HHV-6B DNA levels decreased rapidly after infection in all mice. Persistence in the brain was observed with infectious but not heat-inactivated HHV-6A. Immunohistological studies revealed the presence of infiltrating lymphocytes in periventricular areas of the brain of HHV-6A-infected mice. Furthermore, HHV-6A stimulated the production of a panel of proinflammatory chemokines in primary brain glial cultures, including CCL2, CCL5, and CXCL10, and induced the expression of CCL5 in the brains of HHV-6A-infected mice. HHV-6A-induced production of chemokines in the primary glial cultures was dependent on the stimulation of toll-like receptor 9 (TLR9). Finally, HHV-6A induced signaling through human TLR9 as well, extending observations from the murine model to human infection. Altogether, this study presents a first murine model for HHV-6A-induced brain infection and suggests a role for TLR9 in the HHV-6A-initiated production of proinflammatory chemokines in the brain, opening novel perspectives for the study of virus-associated neuropathology.
HHV-6 infection has been related to neuroinflammatory diseases; however, the lack of a suitable small-animal infection model has considerably hampered further studies of HHV-6-induced neuropathogenesis. In this study, we have characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of CD46 transgenic mice with HHV-6A resulted in long-term persistence of viral DNA in the brains of infected animals and was followed by lymphocyte infiltration and upregulation of the CCL5 chemokine in the absence of clinical signs of disease. The secretion of a panel of chemokines was increased after infection in primary murine brain glial cultures, and the HHV-6-induced chemokine expression was inhibited when TLR9 signaling was blocked. These results describe the first murine model for HHV-6A-induced brain infection and suggest the importance of the TLR9 pathway in HHV-6A-initiated neuroinflammation.
Background
The pathological determinism of H. pylori infection is explained by complex interplay between bacterial virulence and host inflammatory response. In a large prospective multicenter ...clinical study, Th17 response, expression of antimicrobial peptides (AMPs), cagA and vacA status, and bacterial density were investigated in the gastric mucosa of H. pylori ‐infected patients.
Materials and methods
Gastric inflammatory response was analyzed by RT‐qPCR for quantification of Th17 cytokines (IL‐17A, IL‐22), CXCL‐8, and AMPs (BD2 and S100A9) mRNA levels in gastric biopsies. Detection and genotyping of H. pylori strains were achieved by bacterial culture and PCR.
Results
Among 787 patients screened for H. pylori, 269 were analyzed (147 H. pylori ‐infected and 122 uninfected patients). In H. pylori ‐infected patients, distribution was 83 gastritis, 12 duodenal ulcers, 5 gastric ulcers, and 47 precancerous and cancerous lesions. CXCL‐8, IL‐17A, BD2, and S100A9 mRNA levels were significantly increased in H. pylori ‐infected patients but, surprisingly, IL‐22 was not, and no difference was shown between H. pylori ‐related diseases. A positive correlation was identified between S100A9 expression and bacterial density. Although expression of the virulence genes cagA and vacA did not impact inflammatory response, patients infected with a cagA‐positive strain were associated with severe H. pylori ‐related diseases.
Conclusion
This study showed that CXCL‐8, IL‐17A, and AMPs are not differently expressed according to the various H. pylori ‐related diseases. The clinical outcome determinism of H. pylori infection is most likely not driven by gastric inflammation but rather tends to mainly influenced by bacterial virulence factors.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The development of three‐dimensional models of reconstituted mouse epidermis (RME) has been hampered by the difficulty to maintain murine primary keratinocyte cultures and to achieve a complete ...epidermal stratification. In this study, a new protocol is proposed for the rapid and convenient generation of RME, which reproduces accurately the architecture of a normal mouse epidermis. During RME morphogenesis, the expression of differentiation markers such as keratins, loricrin, filaggrin, E‐cadherin and connexins was followed, showing that RME structure at day 5 was similar to those of a normal mouse epidermis, with the acquisition of the natural barrier function. It was also demonstrated that RME responded to skin‐relevant proinflammatory cytokines by increasing the expression of antimicrobial peptides and chemokines, and inhibiting epidermal differentiation markers, as in the human system. This new model of RME is therefore suitable to investigate mouse epidermis physiology further and opens new perspectives to generate reconstituted epidermis from transgenic mice.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The complement system is known to contribute to demyelination in multiple sclerosis and experimental autoimmune encephalomyelitis. However, there are few data concerning the natural adjuvant effect ...of C3d on the humoral response when it binds to myelin Ags. This study addresses the effect of C3d binding to the myelin oligodendrocyte glycoprotein (MOG) in the induction of experimental autoimmune encephalomyelitis in C57BL/6J mice. Immunization with human MOG coupled to C3d was found to accelerate the appearance of clinical signs of the disease and to enhance its severity compared with MOG-immunized mice. This finding was correlated with an increased infiltration of leukocytes into the central nervous system accompanied by increased complement activation and associated with areas of demyelination and axonal loss. Furthermore, B cell participation in the pathogenesis of the disease was determined by their increased capacity to act as APCs and to form germinal centers. Consistent with this, the production of MOG-specific Abs was found to be enhanced following MOG/C3d immunization. These results suggest that binding of C3d to self-Ags could increase the severity of an autoimmune disease by enhancing the adaptive autoimmune response.
Cutaneous squamous cell carcinoma (cSCC) is the second most common keratinocyte malignancy and accounts for 20% of skin cancer deaths. Cancer is closely related to inflammation, but the contribution ...of the tumor microenvironment to cSCC development is poorly understood. We previously showed that oncostatin M (OSM), a cytokine belonging to the IL-6 family, promotes normal keratinocyte proliferation and migration, skin inflammation, and epidermal hyperplasia, both
and
. Here, we show that OSM is overexpressed in human cSCC and is associated with type 1 immune polarization.
, OSM induced STAT-3 and ERK signaling, modified the expression of genes involved in cytokine signaling, proliferation, inhibition of apoptosis, and immune responses, and promoted proliferation and migration of malignant keratinocyte PDVC57 cells. PDVC57 cells grafted in the skin of mice led to rapid cSCC development, associated with OSM expression by tumor-infiltrating neutrophils. Finally, the absence of OSM (OSM-KO mice) led to a 30% reduction of tumor size and reduced M2 polarization in the tumor microenvironment. Globally, these results support a pro-tumoral role of OSM in cSCC development and suggest that a new therapeutic approach targeting this cytokine could be considered.
Temporin-SHa (SHa) is a small cationic host defence peptide (HDP) produced in skin secretions of the Sahara frog Pelophylax saharicus. This peptide has a broad-spectrum activity, efficiently ...targeting bacteria, parasites and viruses. Noticeably, SHa has demonstrated an ability to kill Leishmania infantum parasites (amastigotes) within macrophages. Recently, an analog of SHa with an increased net positive charge, named K
SHa, has been designed to improve those activities. SHa and K
SHa were both shown to exhibit leishmanicidal activity mainly by permeabilization of cell membranes but could also induce apoptotis-like death. Temporins are usually poorly active against Gram-negative bacteria whereas many of these species are of public health interest. Among them, Legionella pneumophila, the etiological agent of Legionnaire's disease, is of major concern. Indeed, this bacterium adopts an intracellular lifestyle and replicate inside alveolar macrophages likewise inside its numerous protozoan hosts. Despite several authors have studied the antimicrobial activity of many compounds on L. pneumophila released from host cells, nothing is known about activity on intracellular L. pneumophila within their hosts, and subsequently mechanisms of action that could be involved. Here, we showed for the first time that SHa and K
SHa were active towards several species of Legionella. Both peptides displayed bactericidal activity and caused a loss of the bacterial envelope integrity leading to a rapid drop in cell viability. Regarding amoebae and THP-1-derived macrophages, SHa was less toxic than K
SHa and exhibited low half maximal lethal concentrations (LC
). When used at non-toxic concentration (6.25 µM), SHa killed more than 90% L. pneumophila within amoebae and around 50% within macrophages. Using SHa labeled with the fluorescent dye Cy5, we showed an evenly diffusion within cells except in vacuoles. Moreover, SHa was able to enter the nucleus of amoebae and accumulate in the nucleolus. This subcellular localization seemed specific as macrophages nucleoli remained unlabeled. Finally, no modifications in the expression of cytokines and HDPs were recorded when macrophages were treated with 6.25 µM SHa. By combining all data, we showed that temporin-SHa decreases the intracellular L. pneumophila load within amoebae and macrophages without being toxic for eukaryotic cells. This peptide was also able to reach the nucleolus of amoebae but was not capable to penetrate inside vacuoles. These data are in favor of an indirect action of SHa towards intracellular Legionella and make this peptide a promising template for further developments.
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