Gastric digestion of the sweet-tasting plant protein thaumatin releases bitter peptides that reduce H. pylori induced pro-inflammatory IL-17A release via the TAS2R16 bitter taste receptor.

About half of the world's population is infected with the bacterium Helicobacter pylori. For colonization, the bacterium neutralizes the low gastric pH and recruits immune cells to the stomach. The immune cells secrete cytokines, i.e., the pro-inflammatory IL-17A, which directly or indirectly damage surface epithelial cells. Since (I) dietary proteins are known to be digested into bitter tasting peptides in the gastric lumen, and (II) bitter tasting compounds have been demonstrated to reduce the release of pro-inflammatory cytokines through functional involvement of bitter taste receptors (TAS2Rs), we hypothesized that the sweet-tasting plant protein thaumatin would be cleaved into anti-inflammatory bitter peptides during gastric digestion. Using immortalized human parietal cells (HGT-1 cells), we demonstrated a bitter taste receptor TAS2R16-dependent reduction of a H. pylori-evoked IL-17A release by up to 89.7 ± 21.9% (p ≤ 0.01). Functional involvement of TAS2R16 was demonstrated by the study of specific antagonists and siRNA knock-down experiments.

Co-immunization with DNA vaccines encoding yidR and IL-17 augments host immune response against Klebsiella pneumoniae infection in mouse model.

Klebsiella pneumoniae is an important gram-negative bacterium that causes severe respiratory and healthcare-associated infections. Although antibiotic therapy is applied to treat severe infections caused by K. pneumoniae, drug-resistant isolates pose a huge challenge to clinical practices owing to adverse reactions and the mismanagement of antibiotics. Several studies have attempted to develop vaccines against K. pneumoniae, but there are no licensed vaccines available for the control of K. pneumoniae infection. In the current study, we constructed a novel DNA vaccine, pVAX1-YidR, which encodes a highly conserved virulence factor YidR and a recombinant expression plasmid pVAX1-IL-17 encoding Interleukin-17 (IL-17) as a molecular adjuvant. Adaptive immune responses were assessed in immunized mice to compare the immunogenicity of the different vaccine schemes. The results showed that the targeted antigen gene was expressed in HEK293T cells using an immunofluorescence assay. Mice immunized with pVAX1-YidR elicited a high level of antibodies, induced strong cellular immune responses, and protected mice from K. pneumoniae challenge. Notably, co-immunization with pVAX1-YidR and pVAX1-IL-17 significantly augmented host adaptive immune responses and provided better protection against K. pneumoniae infections in vaccinated mice. Our study demonstrates that combined DNA vaccines and molecular adjuvants is a promising strategy to develop efficacious antibacterial vaccines against K. pneumoniae infections.

Incidence of Uveitis in Patients With Axial Spondylarthritis Treated With Biologics or Targeted Synthetics: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Anterior uveitis is a common extra-articular manifestation of axial spondyloarthritis (AxSpA). We set to evaluate the risk of anterior uveitis (AU) with biologics and synthetic disease-modifying drugs in AxSpA. METHODS: We conducted a systematic review and meta-analysis to identify phase II/III double-blinded randomized controlled trials of anti-tumor necrosis factor (TNF) monoclonal antibodies (mAb), anti-interleukin-17 (anti-IL-17), and Janus kinase inhibitors (JAKi) in AxSpA. Patient-exposure years (PEY) were calculated using the per-protocol approach. Incidence rate (IR) of AU/100 person-years were calculated by treatment group using the random effects approach. Network meta-analysis (NMA) was used to estimate risk of AU in treatment groups, expressed as IR ratios (IRRs). Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS: Forty-four trials were included: 17 anti-TNF mAb (1,004 PEY), 9 etanercept (180 PEY), 13 anti-IL-17 (1,834 PEY), and 6 JAKi (331 PEY). The IR of AU were as follows for anti-TNF mAb: 4.1, 95% confidence interval (CI) 0-8.5; etanercept: 5.4, 95% CI 0-16.0; anti-IL-17: 2.8, 95% CI 1.6-4.1; JAKi: 1.5, 95% CI 0.0-3.0; and placebo: 10.8, 95% CI 7.4-14.1. In NMA, IRRs of treatments compared with placebo were as follows for anti-TNF mAb: 0.32, 95% CI 0.10-1.04; etanercept 0.42, 95% CI 0.08-2.38; anti-IL-17: 0.43, 95% CI 0.19-0.98; and JAKi: 0.32, 95% CI 0.06-1.67. Comparisons between anti-TNF mAb, anti-IL-17, and JAKi did not demonstrate any significant difference in AU risk. Using the surface under the cumulative ranking curve approach to rank AU risk, anti-TNF mAbs were associated with the lowest risk followed by JAKi, anti-IL-17, and etanercept. All treatments were ranked superior to placebo. CONCLUSION: Anti-TNF mAbs, JAKi, and anti-IL-17 appear protective against AU events in individuals with AxSpA, with no significant differences in risk of AU between treatments.

Molecular characterization and expression of twenty interleukin-17 transcripts in the common Chinese cuttlefish (Sepiella japonica) in response to Vibrio harveyi infection.

The common Chinese cuttlefish (Sepiella japonica) is an essential species for stock enhancement by releasing juveniles in the East China Sea now. S. japonica is susceptible to bacterial diseases during parental breeding. In vertebrates, Interleukin-17 (IL-17) cytokine family plays critical roles in both acute and chronic inflammatory responses. In Cephalopoda, few studies have been reported on IL-17 genes so far. In this study, twenty IL-17 transcripts obtained from S. japonica were divided into eight groups (designated as Sj_IL-17-1 to Sj_IL-17-8). Multiple alignment analysis showed that IL-17s in S. japonica and human both contained four ß-folds (ß1-ß4), except for Sj_IL-17-6 with two ß-folds (ß1 and ß2), and the third and fourth ß-folds of Sj_IL-17-5 and Sj_IL-17-8 were longer than those of other Sj_IL-17. Protein structure and conserved motifs analysis demonstrated that Sj_IL-17-5 and Sj_IL-17-6 displayed different protein structure with respect to other six Sj_IL-17 proteins. The homology and phylogenetic analysis of amino acids showed that Sj_IL-17-5, Sj_IL-17-6 and Sj_IL-17-8 had low homology with the other five Sj_IL-17s. Eight Sj_IL-17 mRNAs were ubiquitously expressed in ten examined tissues, with dominant expression in the hemolymph. qRT-PCR data showed that the mRNA expression levels of Sj_IL-17-2, Sj_IL-17-3, Sj_IL-17-6, and Sj_IL-17-8 were significantly up-regulated in infected cuttlefishes, and Sj_IL-17-2, Sj_IL-17-6, Sj_IL-17-7, and Sj_IL-17-8 mRNAs Awere significantly up-regulated after bath infection of Vibrio harveyi, suggesting that certain Sj_IL-17s were involved in the immune response of S. japonica against V. harveyi infection. These results implied that Sj_IL-17s were likely to have distinct functional diversification. This study aims to understand the involvement of Sj_IL-17 genes in immune responses of cuttlefish against bacterial infections.

IL-17A plays a critical role in RSV infection in children and mice.

BACKGROUND: IL-17A is a pleiotropic cytokine and intimately associated with asthma, but its role in respiratory syncytial virus (RSV) infection is conflicting in the literature. METHODS: Children hospitalized in the respiratory department with RSV infection during RSV pandemic season of 2018-2020 were included. Nasopharyngeal aspirates were collected for pathogen and cytokines determination. In the murine model, RSV intranasal administrations were performed in wild-type and IL-17A-/- mice. Leukocytes and cytokines in bronchoalveolar lavage fluid (BALF), lung histopathology, and airway hyperresponsiveness (AHR) were measured. RORγt mRNA and IL-23R mRNA were semi-quantified by qPCR. RESULTS: IL-17A increased significantly in RSV-infected children and was positively associated with pneumonia severity. In the murine model, IL-17A significantly increased in BALF of mice with RSV infection. Airway inflammation, lung tissue damage and AHR were significantly alleviated in wild-type mice following IL-17A neutralization and in the IL-17A-/- mice. IL-17A decreased by removing CD4+ T cells but increased by depleting CD8+ T cells. IL-6, IL-21, RORγt mRNA and IL-23R mRNA dramatically increased in parallel with the rise of IL-17A. CONCLUSIONS: IL-17A contributes to the airway dysfunctions induced by RSV in children and murine. CD3+CD4+T cells are its major cellular sources and the IL-6/IL-21-IL-23R-RORγt signaling pathway might participate in its regulation.

Adverse events associated with anti-IL-17 agents for psoriasis and psoriatic arthritis: a systematic scoping review.

Background: Anti-interleukin (IL)-17 biological agents (BAs) have significant efficacy in the treatment of psoriasis and psoriatic arthritis; however, adverse events (AEs) are common, and their safety has not been systematically evaluated. Objectives: The purpose of this systematic review and meta-analysis was to summarize the number and corresponding rates of AEs caused by anti-IL-17 BAs in patients with psoriasis and psoriatic arthritis to improve clinical decision-making regarding their use. Methods: PubMed, Embase, Cochrane Library, and Web of Science databases were independently searched by three authors for articles on the treatment of psoriasis with anti-IL-17 BAs that were published before March 1, 2022, and included at least one AE. Dichotomous variables and 95% confidence intervals (CI) were analyzed using R software (version 4.1.3) and the Meta and Metafor software packages. Funnel plots and meta-regression were used to test for the risk of bias, I2 was used to assess the magnitude of heterogeneity, and subgroup analysis was used to reduce heterogeneity. Results: A total of 57 studies involving 28,424 patients with psoriasis treated with anti-IL-17 BAs were included in the meta-analysis. Subgroup analysis showed that anti-IL-17A (73.48%) and anti-IL-17A/F (73.12%) BAs were more likely to cause AEs than anti-IL-17R BAs (65.66%). The incidence of AEs was as high as 72.70% with treatment durations longer than one year, and long-term use of medication had the potential to lead to mental disorders. Infection (33.16%), nasopharyngitis (13.74%), and injection site reactions (8.28%) were the most common AEs. Anti-IL-17 BAs were most likely to cause type α (33.52%) AEs. Type δ AEs (1.01%) were rarely observed. Conclusions: Anti-IL-17 BAs used for the treatment of psoriasis and psoriatic arthritis caused a series of AEs, but the symptoms were generally mild.

GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology.

There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.

The Airway Microbiome-IL-17 Axis: a Critical Regulator of Chronic Inflammatory Disease.

The respiratory tract is home to a diverse microbial community whose influence on local and systemic immune responses is only beginning to be appreciated. Increasing reports have linked changes in this microbiome to a range of pulmonary and extrapulmonary disorders, including asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. Central to many of these findings is the role of IL-17-type immunity as an important driver of inflammation. Despite the crucial role played by IL-17-mediated immune responses in protection against infection, overt Th17 cell responses have been implicated in the pathogenesis of several chronic inflammatory diseases. However, our knowledge of the influence of bacteria that commonly colonise the respiratory tract on IL-17-driven inflammatory responses remains sparse. In this article, we review the current knowledge on the role of specific members of the airway microbiota in the modulation of IL-17-type immunity and discuss how this line of research may support the testing of susceptible individuals and targeting of inflammation at its earliest stages in the hope of preventing the development of chronic disease.

Exosomes with FOXP3 from gene-modified dendritic cells ameliorate the development of EAE by regulating the balance of Th/Treg.

Objective: To investigate the efficiency and potential mechanisms of exosomes from dendritic cells (DCs) transfected with Forkhead box protein P3 (FOXP3) in the development of experimental autoimmune encephalomyelitis (EAE). Method: Mouse bone marrow-derived immature DCs were loaded with adenovirus carrying FOXP3 gene, and exosomes were generated. Then the exosomes with FOXP3 (FOXP3-EXOs) were co-cultured with CD4+T cell in vitro to evaluate their potential on CD4+T cell proliferation and differentiation, and injected into EAE mice to assess their effects on the development of EAE. Result: FOXP3-EXOs were effective to inhibit the CD4+T cell proliferation and the production of Interferon gamma (IFN-γ), interleukin (IL)-6, and IL-17, while they promoted the production of IL-10 in vitro. Moreover, FOXP3-EXOs treatment significantly decreased the neurological scores, reduced the infiltration of inflammatory cells into the spinal cord, and decreased demyelination in comparison to saline and Con-EXOs treated EAE mice. Moreover, the FOXP3-EXOs treatment resulted in obvious increases in the levels of regulatory T (Treg) cells and IL-10, whereas levels of T helper 1 (Th1) cells, Th17 cells, IFN-γ, IL-6, and IL-17 decreased significantly in the splenocyte culture of EAE mice. Conclusion: The present study preliminarily investigated the effects and potential mechanisms of FOXP3-EXOs in EAE and revealed that the FOXP3-EXOs could inhibit the production of Th1 and Th17 cells and promote the production of Treg cells as well as ameliorate the development of EAE. The neuroprotective effects of FOXP3-EXOs on EAE are likely due to the regulation of Th/Treg balance.

Helminth species dependent effects on Th1 and Th17 cytokines in active tuberculosis patients and healthy community controls.

Despite that the impact of different helminth species is not well explored, the current dogma states that helminths affect the Th1/Th2 balance which in turn affects the risk of tuberculosis (TB) reactivation and severity of disease. We investigated the influence of helminth species on cytokine profiles including IL-17A in TB patients and healthy community controls (CCs). In total, 104 newly diagnosed pulmonary TB patients and 70 HIV negative and QuantiFERON negative CCs in Gondar, Ethiopia were included following helminth screening by stool microscopy. Plasma samples and ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with purified protein derivative (PPD) and Staphylococcus enterotoxin B (SEB) was used to determine cytokine profiles by cytometric bead array. In CCs, Ascaris lumbricoides or Schistosoma mansoni infections were associated with an impaired Th1-type response (IFN-gamma, IL-6 and TNF-alpha) in PBMCs mainly with SEB stimulations, whereas in TB patients only hookworm infection showed a similar pattern. Among CCs, the IL-17A response in PBMCs stimulated with SEB was higher only for S. mansoni, whereas in TB patients, the elevated systemic IL-17A plasma level was significantly suppressed in hookworm infected TB patients compared to patients without helminth coinfection. Following treatment of TB and helminth infection there was a general decrease in ex vivio IL-10 and TNF-alpha production in unstimulated, PPD or SEB stimulated PBMCs that was the most pronounced and significant in TB patients infected with S. mansoni, whereas the follow-up levels of IFN-gamma and IL-17A was significantly increased only in TB patients without helminth coinfection from PBMCs stimulated mainly with SEB. In summary, in addition to confirming helminth specific effects on the Th1/Th2 response before and after TB treatment, our novel finding is that IL-17A was impaired in helminth infected TB patients especially for hookworm, indicating a helminth species-specific immunoregulatory effect on IL-17A which needs to be further investigated.

From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target?

The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-γ) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-γ in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-γ-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4+CD161+CCR6+CXCR3+IL-17+IFN-y+ (Th17.1) and CD4+CD161+CCR6+CXCR3+IL-17-IFN-y+ (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target.

IL-17RA receptor signaling contributes to lung inflammation and parasite burden during Toxocara canis infection in mice.

IL-17 is a cytokine produced by innate and acquired immunity cells that have an action against fungi and bacteria. However, its action in helminth infections is unclear, including in Toxocara canis infection. Toxocariasis is a neglected zoonosis representing a significant public health problem with an estimated seroprevalence of 19% worldwide. In the present study, we describe the immunopathological action of IL-17RA in acute T. canis infection. C57BL/6j (WT) and IL-17RA receptor knockout (IL-17RA-/-) mice were infected with 1000 T. canis eggs. Mice were evaluated 3 days post-infection for parasite load and white blood cell count. Lung tissue was harvested for histopathology and cytokine expression. In addition, we performed multiparametric flow cytometry in the BAL and peripheral blood, evaluating phenotypic and functional changes in myeloid and lymphoid populations. We showed that IL-17RA is essential to control larvae load in the lung; however, IL-17RA contributed to pulmonary inflammation, inducing inflammatory nodular aggregates formation and presented higher pulmonary IL-6 levels. The absence of IL-17RA was associated with a higher frequency of neutrophils as a source of IL-4 in BAL, while in the presence of IL-17RA, mice display a higher frequency of alveolar macrophages expressing the same cytokine. Taken together, this study indicates that neutrophils may be an important source of IL-4 in the lungs during T. canis infection. Furthermore, IL-17/IL-17RA axis is important to control parasite load, however, its presence triggers lung inflammation that can lead to tissue damage.

Tuscany consensus for the treatment of moderate-severe psoriasis: update and focus on practical guidelines for place in therapy of anti-IL-17 and anti-IL-23 biologics.

Psoriasis is a common chronic skin disease characterized by a worldwide distribution and a natural tendency towards progression. According to the many clinical forms, the extension of the disease and the many comorbidities, almost the 20% of the patients require a systemic treatment. Biologics have greatly changed the ongoing of psoriasis and the quality of life of psoriasis patients. After the anti-TNF-alpha, which were the first biologics in use for psoriasis, the improvement in knowledge of the pathogenetic mechanisms underlying the disease has led to the development of a series of more specific therapies for psoriasis. This "second generation" of biologics includes the interleukin (IL)-12/23 inhibitor ustekinumab, IL-17 inhibitors (secukinumab and ixekizumab), the IL-17 receptor A (IL-17RA) antagonist brodalumab, and the IL-23 inhibitors guselkumab, risankizumab and tildrakizumab. This study represents an update of the Tuscany consensus focused on the use of new drugs, such as anti-IL-17 and anti-IL-23 in moderate-to-severe psoriasis and their correct place in therapy according to specific clinical requests and in full respect of the current financial restrictions.

The effects of Malassezia in the activation of Interleukin (IL)-23/IL-17 axis in Psoriasis.

We explore the association of Malassezia and IL-23/IL-17 axis in the skin lesions of patients with Psoriasis. From October 2018 to October 2020, 202 psoriasis patients were hospitalized in the dermatology department of Yantaishan hospital. The patients' skin lesions were collected, and Malassezia-specific mRNA in the skin lesions was determined. The patients were subdivided into Malassezia high and low distribution groups as per the Malassezia-specific mRNA results. Psoriasis Area and Severity Index (PASI) scores between the two groups were performed. LL-37, IL-23, IL-17A, and tumor necrosis factor α (TNF-α) expression in the skin lesions of the two groups were determined. Malassezia mRNA and the correlation of LL-37 with inflammatory factors TNF-α, IL-23, and IL-17A were determined. The relevance of inflammatory factors, Malassezia infection, and LL-37 content with PASI score were studied. The Malassezia high distribution group was treated with etoconazole, and the effects of treatment on the PASI score, IL-23, TNF-α, and IL-17A were determined. The PASI score, neutrophil, eosinophil, and peripheral blood white blood cell counts, and lgG in the Malassezia high distribution group were significantly higher than in the low distribution group (P<0.05). IL-23, LL-37, TNF-α, and IL-17A levels in the Malassezia high distribution group were significantly higher than in the low distribution group (P<0.05). Malassezia and LL-37 levels had a moderate positive correlation (R=0.5009, P<0.0001). Malassezia and LL-37, IL-17A, TNF-a, and IL- 23 correlated positively. Malassezia, IL-17A, LL37, TNF-a, and IL-23 correlated positively with the PASI score of Psoriasis. Ketoconazole therapy inhibited the PASI score, IL-23, TNF-a, and IL-17A expressions in patients. Malassezia enhances the progression of Psoriasis through the aberrant activation of the IL-23/IL-17 axis.

IL-25 blockade augments antiviral immunity during respiratory virus infection.

IL-25 is implicated in the pathogenesis of viral asthma exacerbations. However, the effect of IL-25 on antiviral immunity has yet to be elucidated. We observed abundant expression and colocalization of IL-25 and IL-25 receptor at the apical surface of uninfected airway epithelial cells and rhinovirus infection increased IL-25 expression. Analysis of immune transcriptome of rhinovirus-infected differentiated asthmatic bronchial epithelial cells (BECs) treated with an anti-IL-25 monoclonal antibody (LNR125) revealed a re-calibrated response defined by increased type I/III IFN and reduced expression of type-2 immune genes CCL26, IL1RL1 and IL-25 receptor. LNR125 treatment also increased type I/III IFN expression by coronavirus infected BECs. Exogenous IL-25 treatment increased viral load with suppressed innate immunity. In vivo LNR125 treatment reduced IL-25/type 2 cytokine expression and increased IFN-ß expression and reduced lung viral load. We define a new immune-regulatory role for IL-25 that directly inhibits virus induced airway epithelial cell innate anti-viral immunity.

The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription.

Aberrant IL-17A expression together with reduced IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while promoting their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K, activation of the mTORC1/HIF-1α/RORγt pathway and induction of Th17-cell differentiation. Additionally, SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, bound directly to the Sirt2 promoter and promoted its transcription. AK-7, a SIRT2 inhibitor, limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2-producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies.

Epidermal clearance of Candida albicans is mediated by IL-17 but independent of fungal innate immune receptors.

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.

Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria.

Antibiotics are a modifiable iatrogenic risk factor for the most common human nosocomial fungal infection, invasive candidiasis, yet the underlying mechanisms remain elusive. We found that antibiotics enhanced the susceptibility to murine invasive candidiasis due to impaired lymphocyte-dependent IL-17A- and GM-CSF-mediated antifungal immunity within the gut. This led to non-inflammatory bacterial escape and systemic bacterial co-infection, which could be ameliorated by IL-17A or GM-CSF immunotherapy. Vancomycin alone similarly enhanced the susceptibility to invasive fungal infection and systemic bacterial co-infection. Mechanistically, vancomycin reduced the frequency of gut Th17 cells associated with impaired proliferation and RORγt expression. Vancomycin's effects on Th17 cells were indirect, manifesting only in vivo in the presence of dysbiosis. In humans, antibiotics were associated with an increased risk of invasive candidiasis and death after invasive candidiasis. Our work highlights the importance of antibiotic stewardship in protecting vulnerable patients from life-threatening infections and provides mechanistic insights into a controllable iatrogenic risk factor for invasive candidiasis.

Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model.

Psoriasis is a chronic dermal inflammatory disease with a world-wide prevalence in which different immune/non-immune cells, e.g. T cells, macrophages, neutrophils, and keratinocytes play a decisive role. These immune cells interact among themselves by releasing multiple mediators which eventually cause characteristic psoriatic plaques in the skin. T cells are reported to be significant contributors to psoriatic inflammation through release of multiple cytokines which are controlled by several kinases, one of them being Lymphocyte-specific protein tyrosine kinase (Lck). Lck has been reported to be crucial for expression/production of several key inflammatory cytokines though modulation of several other kinases/transcription factors in T cells. Therefore, in this investigation, effect of Lck inhibitor, A-770041 was examined on PLCγ, p38MAPK, NFATc1, NFkB and STAT3, TNF-α, IFN-γ, Foxp3, IL-17A, in CD4+ T cells in imiquimod (IMQ)-induced psoriatic inflammation in mice. Results from the present study exhibit that p-Lck expression is enhanced in CD4+ T cells of IMQ-treated mice which is concomitant with enhanced clinical features of psoriatic inflammation (ear/back skin thickness, MPO activity, acanthosis/leukocytic infiltration) and molecular parameters (enhanced expression of p-Lck, p-PLCγ, p-p38-MAPK, NFATc1, p-NFkB, TNF-α, IFN-γ, p-STAT3, and IL-17A in CD4+ T cells). Inhibition of Lck signaling led to amelioration of clinical features of psoriasis through attenuation of Th1/Th17 immune responses and upregulation of Treg cells in IMQ-treated mice. In summary, current investigations reveal that Lck signaling is a crucial executor of inflammatory signaling in CD4+ T cells in the context of psoriatic inflammation. Therefore, Lck inhibition may be pursued as an effective strategy to counteract psoriatic inflammation.