Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.
Keywords: IL-1R r Imiquimod r MyD88 r NLRP3 inflammasome r Skin inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Franck Morel e-mail: f.morel@univ-poitiers.fr IntroductionPsoriasis is a chronic inflammatory skin disease estimated to affect 2-3% of the general population [1]. Clinical presentation is usually associated with red, scaly, and raised plaques. These are the C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2848 Hanitriniaina Rabeony et al. Eur. J. Immunol. 2015. 45: 2847-2857 consequences of a marked thickening of the epidermis due to an increased proliferation of keratinocytes (acanthosis), a retention of nuclei in the stratum corneum (parakeratosis) caused by alterations of keratinocyte differentiation leading to reduced or loss of the granular layer, and the presence of inflammatory cell infiltrates in the epidermis and dermis [2]. The inflammatory infiltrate is composed mainly of dendritic cells, macrophages and T cells in the dermis and neutrophils, with some T cells in the epidermis [3]. The combination of this infiltration and acanthosis contributes to the overall thickness of lesions. Therefore, the pathogenesis of psoriasis clearly results from a cross-talk between immune cells, keratinocytes, endothelial cells, and fibroblasts, with the release of growth factors, chemokines, and cytokines required for the induction and the maintenance of this disease [3,4]. An important role of the IL-23/IL-17/IL-22 axis in the induction of psoriasis has become evident, in which IL-23 secreted by some DC is responsible for the production of the Th17-related proinflammatory cytokines . IL-1 family members also play an important role in the regulation of the immune response and dysregulation of their expressions leads to tissue destruction and severe pathological effects, including skin diseases such as psoriasis [5,6]. Clearly, IL-1 is considered as a key player in the initiation and the maintenance of psoriasis by inducing Th17-cell maturation and downstream cytokine production [7,8]. IL-1α and IL-1β, the original members of IL-1 family, recognize IL-1 receptor type 1 (IL-1R1) which leads to the recruitment of the adaptor molecule MyD88 (adaptor protein shared by IL-1R and TLR signaling) and activate transcription factors NF-κB and AP1, whereas the binding of IL-1 receptor antagonist (IL-1Ra) to IL-1R1 totally blocks the biological activity of both proinflammatory molecules 9]. The mature secreted form of IL-1β requires engagement of the protein complexes termed inflammasomes. NLRP3 inflammasome includes the adaptor protein ASC (apoptosis-associated Speck-like protein containing a Caspase recruitment domain) necessary for the activation of the cysteine protease caspase-1, responsible for cleaving pro-IL-1β to mature IL-1β, whereas IL-1α is already biologically active and its processing requires the protease calpain [5]. In vitro studies showed that IL-1α or IL-1β induces the production of CCL...
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.Keywords: Imiquimod · Keratinocyte · Oncostatin M · Psoriasis · Skin inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Jean-François Jégou e-mail: jean-francois.jegou@univ-poitiers.fr IntroductionPsoriasis is the most common inflammatory skin disease affecting 2-3% of the adult population, mainly in developed countries, Eur. J. Immunol. 2016Immunol. . 46: 1737Immunol. -1751 in which patients develop skin lesions characterized by erythematous and scaly plaques [1]. The histological features of psoriatic skins are a thickening of the epidermis resulting from an altered keratinocyte differentiation associated with a hyperplasia at the basement membrane, a hyperkeratosis and a parakeratosis (loss of the granular layer and abnormal presence of cell nuclei in the cornified layer) [1,2]. At the inflammatory site, these alterations of the epidermis are the consequence of a crosstalk between infiltrating immune cells and tissue resident cells (e.g. dermal fibroblasts, epidermal keratinocytes, and resident immune cells) through the release of numerous cytokines. In this complex network of interactions, keratinocytes are now considered to play a key role as bona fide innate immune cells, capable of secreting cytokines, chemokines, and antimicrobial peptides in response to various stimuli [3]. Psoriasis has been reported to be a Th1-and Th17-driven pathology [4]. The IL-23/IL-17 axis plays a crucial role in the pathogenesis of the disease, as demonstrated by the detection of IL-23 producing DCs and the expression of IL-17 and IL-22 by T cells and type 3...
BackgroundAlzheimer’s disease is widely described since the discovery of histopathological lesions in Mrs. Auguste Deter in 1906. However to date, there is no effective treatment to deal with the many cellular and molecular alterations. The complexity is even higher with the growing evidence of involvement of the peripheral blood mononuclear cells (PBMCs). Indeed, monocytes and T cells are shown in the cerebral parenchyma of AD patients, and these cells grafted to the periphery are able to go through the blood-brain barrier (BBB) in transgenic mouse models. It is known that BBB is disrupted at a late stage of AD. Chemokines represent major regulators of the transmigration of PBMCs, but many data were obtained on AD animal models. No data are available on the role of AD BBB in a healthy brain parenchyma. Therefore, the purpose of this study was to analyze the longitudinal chemokine profile expression in a BBB model from AD transgenic mice versus wild-type (WT) mice.MethodsA primary mouse BBB model was used with a luminal compartment either AD or WT and an abluminal compartment WT consisting of astrocytes and microglia. PBMCs were extracted by a ficoll gradient and incubated in the transwell with a direct contact with the luminal side, including the endothelial cells and pericytes. Then, the complete BBB model was incubated during 48 h, before supernatants and cell lysates were collected. Chemokines were quantified by X-MAP® luminex technology.ResultsAbluminal CX3CL1 production increased in 12-month-old AD BBB while CX3CL1 levels decreased in luminal lysates. CCL3 in luminal compartment increased with aging and was significantly different compared to AD BBB at 12 months. In addition, abluminal CCL2 in 12-month-old AD BBB greatly decreased compared to levels in WT BBB. On the contrary, no modification was observed for CCL4, CCL5, and CXCL10.ConclusionThese first findings highlighted the impact of AD luminal compartment on chemokine signature in a healthy brain parenchyma, suggesting new therapeutic or diagnostic approaches.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1220-7) contains supplementary material, which is available to authorized users.
Mainly known for its role in immune defense and inflammation, interleukin 22 (IL-22) has emerged over the past decade as a cytokine involved in the adaptation of stem/progenitor cell activity for tissue homeostasis and repair. IL-22 is present in the brain, which harbors neural stem cells (NSC) in specific niches of which the ventricular-subventricular zone (V-SVZ) is the most important. In this study, we examined a possible effect of IL-22 on NSC in the adult mouse brain. We demonstrate that the IL-22 receptor is expressed in the V-SVZ, mainly in NSC characterized by their SOX2 expression. Addition of IL-22 to V-VSZ cell cultures resulted in an increase in NSC self-renewal, associated with a shift in NSC division mode towards symmetric proliferative divisions at the expense of differentiative divisions. Conversely, loss of IL-22 in knockout mice led to a decrease in neurosphere yield, suggesting a reduction in the NSC population, which was confirmed by the decrease in cells retaining BrdU labeling in IL-22 knockout mice. Our study supports that IL-22 is involved in the development and/or maintenance of V-VSZ NSC and opens new avenues to further investigate the role of IL-22 in NSC biology in health and disease.
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