Suppression of IL-17F, but not of IL-17A, provides protection against colitis by inducing Treg cells through modification of the intestinal microbiota.

The cytokines IL-17A and IL-17F have 50% amino-acid identity and bind the same receptor; however, their functional differences have remained obscure. Here we found that Il17f-/- mice resisted chemically induced colitis, but Il17a-/- mice did not, and that Il17f-/- CD45RBhiCD4+ T cells induced milder colitis in lymphocyte-deficient Rag2-/- mice, accompanied by an increase in intestinal regulatory T cells (Treg cells). Clostridium cluster XIVa in colonic microbiota capable of inducing Treg cells was increased in both Il17f-/- mice and mice given transfer Il17f-/- T cells, due to decreased expression of a group of antimicrobial proteins. There was substantial production of IL-17F, but not of IL-17A, not only by naive T cells but also by various colon-resident cells under physiological conditions. Furthermore, antibody to IL-17F suppressed the development of colitis, but antibody to IL-17A did not. These observations suggest that IL-17F is an effective target for the treatment of colitis.

Gut-Busters: IL-17 Ain't Afraid of No IL-23.

Interleukin-23 (IL-23) is considered a critical regulator of IL-17 in lymphocytes. Whereas antibodies targeting IL-23 ameliorate colitis, IL-17 neutralization exacerbates disease. In this issue, Cua and colleagues and Maxwell and colleagues show that IL-17 maintains intestinal barrier integrity, helping explain this dichotomy (Lee et al., 2015; Maxwell et al., 2015).

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.

Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability.

Whether interleukin-17A (IL-17A) has pathogenic and/or protective roles in the gut mucosa is controversial and few studies have analyzed specific cell populations for protective functions within the inflamed colonic tissue. Here we have provided evidence for IL-17A-dependent regulation of the tight junction protein occludin during epithelial injury that limits excessive permeability and maintains barrier integrity. Analysis of epithelial cells showed that in the absence of signaling via the IL-17 receptor adaptor protein Act-1, the protective effect of IL-17A was abrogated and inflammation was enhanced. We have demonstrated that after acute intestinal injury, IL-23R(+) γδ T cells in the colonic lamina propria were the primary producers of early, gut-protective IL-17A, and this production of IL-17A was IL-23 independent, leaving protective IL-17 intact in the absence of IL-23. These results suggest that IL-17-producing γδ T cells are important for the maintenance and protection of epithelial barriers in the intestinal mucosa.

CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts.

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose-response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.

Novel role for caspase recruitment domain family member 14 and its genetic variant rs11652075 in skin filaggrin homeostasis.

BACKGROUND: Low epidermal filaggrin (FLG) is a risk factor for atopic dermatitis (AD) and allergic comorbidity. FLG mutations do not fully explain the variation in epidermal FLG levels, highlighting that other genetic loci may also regulate FLG expression. OBJECTIVE: We sought to identify genetic loci that regulate FLG expression and elucidate their functional and mechanistic consequences. METHODS: A genome-wide association study of quantified skin FLG expression in lesional and baseline non(never)-lesional skin of children with AD in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort was conducted. Clustered regularly interspaced short palindromic repeat approaches were used to create isogenic human keratinocytes differing only at the identified variant rs11652075, and caspase recruitment domain family member 14 (CARD14)-deficient keratinocytes for subsequent mechanistic studies. RESULTS: The genome-wide association study identified the CARD14 rs11652075 variant to be associated with FLG expression in non(never)-lesional skin of children with AD. Rs11652075 is a CARD14 expression quantitative trait locus in human skin and primary human keratinocytes. The T variant destroys a functional cytosine-phosphate-guanine site, resulting in reduced cytosine-phosphate-guanine methylation at this site (but not neighboring sites) in TT and CT compared with CC primary human keratinocytes and Mechanisms of Progression of Atopic Dermatitis to Asthma in Children children's skin samples, and rs11652075 increases CARD14 expression in an allele-specific fashion. Furthermore, studies in clustered regularly interspaced short palindromic repeat-generated CC and TT isogenic keratinocytes, as well as CARD14-haplosufficient and deficient keratinocytes, reveal that IL-17A regulates FLG expression via CARD14, and that the underlying mechanisms are dependent on the rs11652075 genotype. CONCLUSIONS: Our study identifies CARD14 as a novel regulator of FLG expression in the skin of children with AD. Furthermore, CARD14 regulates skin FLG homeostasis in an rs11652075-dependent fashion.

TH17 cells and corticosteroid insensitivity in severe asthma.

Asthma is classically described as having either a type 2 (T2) eosinophilic phenotype or a non-T2 neutrophilic phenotype. T2 asthma usually responds to classical bronchodilation therapy and corticosteroid treatment. Non-T2 neutrophilic asthma is often more severe. Patients with non-T2 asthma or late-onset T2 asthma show poor response to the currently available anti-inflammatory therapies. These therapeutic failures result in increased morbidity and cost associated with asthma and pose a major health care problem. Recent evidence suggests that some non-T2 asthma is associated with elevated TH17 cell immune responses. TH17 cells producing Il-17A and IL-17F are involved in the neutrophilic inflammation and airway remodeling processes in severe asthma and have been suggested to contribute to the development of subsets of corticosteroid-insensitive asthma. This review explores the pathologic role of TH17 cells in corticosteroid insensitivity of severe asthma and potential targets to treat this endotype of asthma.

IL-17A promotes vascular calcification in an ex vivo murine aorta culture.

BACKGROUND: Vascular calcification is characterized by mineral deposition in the vasculature, which is triggered by chronic systemic inflammation, including psoriasis. Psoriasis is an IL-17A-mediated inflammatory skin disease that is associated with exacerbated vascular calcification and high cardiovascular mortality. Although previous studies have shown that IL-17A induces vascular dysfunction in murine psoriasis models, it has not been clarified whether IL-17A induces vascular calcification. In this study, we investigated the potential vascular calcification-inducing effect of IL-17A in an ex vivo culture system. METHODS: Thoracic and abdominal aortas from mice were cultured in a medium supplemented with inorganic phosphate and were treated with inflammatory cytokines (IL-1ß, TNF-α, IL-6, and IL-17A). Vascular calcification was determined using micro-computed tomography (CT) and histological analyses. RESULTS: IL-1ß, TNF-α, and IL-6 did not significantly promote vascular calcification, whereas IL-17A significantly accelerated vascular calcification of the aorta, as indicated by the increased mineralized volume based on micro-CT analysis. Micro-CT and histological analyses also revealed that the promoting effect of IL-17A on vascular calcification was concentration dependent. CONCLUSIONS: IL-17A significantly promoted vascular calcification in ex vivo cultured aortas, which suggests that this mechanism is involved in the increased risk of cardiovascular events in IL-17A-mediated inflammatory diseases.

Non-immune functions of inflammatory cytokines targeted by anti-psoriatic biologics: a review.

PURPOSE: Psoriasis is an inflammatory disease characterized by skin thickening with silvery white desquamation due to dysregulated inflammatory pathways and elevated levels of inflammatory cytokines. Biologic agents targeting these inflammatory cytokines have brought about significant improvement in clearing psoriatic lesions in patients with moderate-to-severe psoriasis. Moreover, biologics exert both beneficial and detrimental effects on comorbidities in psoriasis, which include increased risk of cardiovascular events, metabolic syndrome, among other conditions. However, non-immune functions of cytokines targeted by biologics, and, hence, the potential risks and benefits of biologics for psoriasis to different organs/systems and comorbidities, have not been well elucidated. RESULTS: This review summarizes current understanding of the pathogenesis of psoriasis-related comorbidities and emerging discoveries of roles of cytokines targeted in psoriasis treatment, including tumor necrosis factor α and interleukins 12, 23, and 17, aiming to complete the safety profile of each biologics and provide therapeutic implications on psoriasis-related comorbidities, and on diseases involving other organs or systems.

Clonal Vγ6+Vδ4+ T cells promote IL-17-mediated immunity against Staphylococcus aureus skin infection.

T cell cytokines contribute to immunity against Staphylococcus aureus, but the predominant T cell subsets involved are unclear. In an S. aureus skin infection mouse model, we found that the IL-17 response was mediated by γδ T cells, which trafficked from lymph nodes to the infected skin to induce neutrophil recruitment, proinflammatory cytokines IL-1α, IL-1ß, and TNF, and host defense peptides. RNA-seq for TRG and TRD sequences in lymph nodes and skin revealed a single clonotypic expansion of the encoded complementarity-determining region 3 amino acid sequence, which could be generated by canonical nucleotide sequences of TRGV5 or TRGV6 and TRDV4 However, only TRGV6 and TRDV4 but not TRGV5 sequences expanded. Finally, Vγ6+ T cells were a predominant γδ T cell subset that produced IL-17A as well as IL-22, TNF, and IFNγ, indicating a broad and substantial role for clonal Vγ6+Vδ4+ T cells in immunity against S. aureus skin infections.

Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis.

Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement.

Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1.

Interleukin-27 (IL-27) is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naive T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription 1 (STAT1)-dependent manner. When cocultured with naive CD4(+) T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, coadministration of naive TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4(+) T cells can restrict differentiation of Th17 cells in trans.

STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer.

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.

The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells.

Interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) drive T helper type 1 (T(H)1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-gamma-induced transcription factor IRF1 was essential in T(H)1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor beta1 subunit (IL-12Rbeta1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4+ T cells. Notably, the IRF1-dependent induction of IL-12Rbeta1 was essential for IFN-gamma-IL-12 signaling but was dispensable for IL-23-IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rbeta1, our data suggest that distinct thresholds of IL-12Rbeta1 expression are required for T(H)1 versus T(H)-17 differentiation.

Functional specialization of interleukin-17 family members.

Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.

Tryptophan (Trp) modulates gut homeostasis via aryl hydrocarbon receptor (AhR).

The intestinal homeostasis is an orchestrated dynamic equilibrium state composed of the coexistence and interactions among the nutrients, microbial flora, and immune system. The intestinal balance disorder can trigger a series of diseases, such as inflammatory bowel disease (IBD). Many of tryptophan (Trp) metabolites, such as kynurenine and indole, generated under a series of endogenous enzymes or microbial metabolism, have been reported enable to bind and activate the aryl hydrocarbon receptor (AhR), this series of process is termed the Trp-AhR pathway. The activated Trp-AhR pathway can induce the expression of downstream cytokines such as interleukin-22 (IL-22) and interleukin-17 (IL-17), thereby regulating the intestinal homeostasis. This review highlights the advance of Trp-AhR pathway in the regulation of intestinal homeostasis and provides some insights for the clinical strategies that expect to effectively prevent and treat gut diseases via intervening the Trp-AhR pathway.

Interleukin-25 regulates matrix metalloproteinase-2 and -9 expression in periodontal fibroblast cells through ERK and P38MAPK pathways.

Interleukin-25 (IL-25) has been recognized as a new member of the IL-17 family and implicated in various inflammatory pathology. We aimed to investigate the effects of IL-25 on the expression of matrix metalloproteinase-2 (MMP-2), MMP-8, and MMP-9 in periodontal fibroblast cells (PFCs), cell migration, cytoskeleton F-actin, and to explore the involved extracellular-regulated protein kinases (ERKs), P38 mitogen-activated protein kinase (P38MAPK) signaling pathways, and IL-17 receptor. To evaluate the expression of MMP-2, MMP-8, MMP-9, and F-actin, PFCs were treated by various doses of IL-25 (0, 20, 50, 100, and 500 ng/ml). Protein expression of extracellular metalloproteinase inducer (EMMPRIN) was also evaluated by western blot. Cell scratches experiment was performed to test the cell migration ability. ERK, P38MAPK, and Jun N-terminal kinase signal pathways and related expression of P-ERK and P-P38MAPK were examined after treatment of different doses of IL-25 and after treatment of inhibitors of ERK and P38MAPK. Immunofluorescence of MMP-2, MMP-9, and F-actin were evaluated after inhibitor treatment. IL-17RB small interfering RNA was used to examine the receptor of IL-25. IL-25 increased the protein expression of MMP-2 and MMP-9. MMP-8 and EMMPRIN expressions were not regulated by IL-25 in PFCs. Positive IF staining extended strongly from the central part to the whole cell. IL-25 mediated MMP-2, MMP-9, F-actin expressions and cell migration were regulated by P38MAPK and ERK pathways, and IL-17RB. SB203580 and U0126 blocked the effects of IL-25 through the inhibition of ERK, P38MAPK, P-ERK, and P-P38MAPK. The data indicate that IL-25 could regulate cell migration, MMP-2, and MMP-9 expression, but not MMP-8 expression, in PFCs. Moreover, the regulation effects were involved in ERK and P38MAPK pathways, and receptor IL-17RB.

Challenges of COVID-19 pandemic for dermatology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the pandemic named coronavirus disease 2019 (COVID-19). The disease causes SARS with a significant morbidity and mortality. We provide a review with a focus on COVID-19 in dermatology. We discuss triage of suspected infectious patients, protection of medical doctors and nurses. We discuss the available data on cutaneous symptoms, although disease-specific symptoms have yet not been observed. COVID-19 is a challenge for the treatment of dermatologic patients, either with severe inflammatory disorders or with skin cancer. The consequences for systemic treatment are obvious but it will be most important to collect the clinical data for a better decision process. Last but not least, education in dermatology for students will not be temporarily possible in the classical settings. COVID-19, although not a skin disease, by itself has an immense impact on dermatology.

Cytokines of the IL-17 family in psoriasis.

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL-17 family are of particular importance. In addition to IL-17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL-17 family also have a proinflammatory effect. This review provides an up-to-date overview of the immunopathogenesis of psoriasis with regard to the six IL-17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.

[Cytokines IL-17, an expanding family used as a target for innovative anti-inflammatory therapies]. / Les cytokines IL-17, une famille en expansion utilisée comme cible pour des thérapies anti-inflammatoires innovantes.

Interleukin 17A is a key effector cytokine in numerous chronic inflammatory diseases. Its neutralization is therapeutically effective and approved in the treatment of chronic inflammatory conditions. Recently, five additional members of the IL-17 cytokine family have been identified, which also contribute to chronic inflammation. Innovative therapeutic strategies therefore aim to simultaneously block not one, but several members of this cytokine family in order to further increase therapeutic efficacy. This article reviews the current knowledge regarding the role of the IL-17 cytokine family in chronic inflammation.

L'interleukine-17 A (IL-17A) est reconnue comme étant une cytokine effectrice clé impliquée dans de nombreuses maladies inflammatoires chroniques. La neutralisation de l'IL-17A est une technique efficace, approuvée dans le traitement des inflammations chroniques. Ces dernières années, cinq autres cytokines IL-17 ont été identifiées, contribuant elles aussi substantiellement à l'inflammation chronique. De nouvelles stratégies thérapeutiques innovantes ont pour but de bloquer simultanément plusieurs cytokines IL-17 afin d'augmenter encore plus l'effet des traitements. Cet article propose une mise à jour des connaissances actuelles concernant le rôle des différentes cytokines de la famille des IL-17 dans l'inflammation chronique.