Altered serum interleukin-17A and interleukin-23A levels may be associated with the pathophysiology and development of generalized anxiety disorder.

In recent times, the pathogenesis of generalized anxiety disorder (GAD) and the influence of pro- and anti-inflammatory cytokines on it have garnered considerable interest. Cytokine research, especially Th-17 cytokine research on GAD patients, is limited. Here, we aim to assess the role of interleukin-17A (IL-17A) and interleukin-23A (IL-23A) in the pathophysiology and development of GAD. This investigation included 50 GAD patients and 38 age-sex-matched healthy controls (HCs). A psychiatrist diagnosed patients with GAD and assessed symptom severity using the DSM-5 and the GAD-7 scales. The serum concentrations of IL-17A and IL-23A were determined using commercially available ELISA kits. GAD patients exhibited elevated levels of IL-17A (77.14 ± 58.30 pg/ml) and IL-23A (644.90 ± 296.70 pg/ml) compared to HCs (43.50 ± 25.54 pg/ml and 334.40 ± 176.0 pg/ml). We observed a positive correlation between disease severity and cytokine changes (IL-23A: r = 0.359, p = 0.039; IL-17A: r = 0.397, p = 0.032). These findings indicate that IL-17A and IL-23A may be associated with the pathophysiology of GAD. ROC analysis revealed moderately higher AUC values (IL-23A: 0.824 and IL-17A: 0.710), demonstrating their potential to discriminate between patients and HCs. Also, the sensitivity values of both cytokines were relatively higher (IL-23A: 80.49% and IL-17A: 77.27%). According to the present findings, there may be an association between peripheral serum levels of IL-17A and IL-23A and the pathophysiology and development of GAD. These altered serum IL-17A and IL-23A levels may play a role in directing the early risk of developing GAD. We recommend further research to ascertain their exact role in the pathophysiology and their performance as risk assessment markers of GAD.

Activation of Antiviral Host Responses against Avian Influenza Virus and Remodeling of Gut Microbiota by rLAB Vector Expressing rIL-17A in Chickens.

Low-pathogenic avian influenza virus (LPAIV) remains the most common subtype of type-A influenza virus that causes moderate to severe infection in poultry with significant zoonotic and pandemic potential. Due to high mutability, increasing drug resistance, and limited vaccine availability, the conventional means to prevent intra- or interspecies transmission of AIV is highly challenging. As an alternative to control AIV infections, cytokine-based approaches to augment antiviral host defense have gained significant attention. However, the selective application of cytokines is critical since unregulated expression of cytokines, particularly proinflammatory ones, can cause substantial tissue damage during acute phases of immune responses. Moreover, depending on the type of cytokine and its impact on intestinal microbiota, outcomes of cytokine-gut microflora interaction can have a critical effect on overall host defense against AIV infections. Our recent study demonstrated some prominent roles of chicken IL-17A (ChIL-17A) in regulating antiviral host responses against AIV infection, however, in an in vitro model. For more detailed insights into ChIL-17A function, in the present study, we investigated whether ChIL-17A-meditated elevated antiviral host responses can translate into effective immune protection against AIV infection in an in vivo system. Moreover, considering the role of gut health in fostering innate or local host responses, we further studied the contributory relationships between gut microbiota and host immunity against AIV infection in chickens. For this, we employed a recombinant lactic acid-producing bacterial (LAB) vector, Lactococcus lactis, expressing ChIL-17A and analyzed the in vivo functionality in chickens against an LPAIV (A/H9N2) infection. Our study delineates that mucosal delivery of rL. lactis expressing ChIL-17A triggers proinflammatory signaling cascades and can drive a positive shift in phylum Firmicutes, along with a marked decline in phylum Actinobacteriota and Proteobacteria, favoring effective antiviral host responses against AIV infection in chickens. We propose that ChIL-17A-mediated selective expansion of beneficial gut microbiota might form a healthy microbial community that augments the effective immune protection against AIV infections in chickens.

Discovery and preclinical evaluation of KYS202004A, a novel bispecific fusion protein targeting TNF-α and IL-17A, in autoimmune disease models.

The treatment of autoimmune and inflammatory diseases often requires targeting multiple pathogenic pathways. KYS202004A is a novel bispecific fusion protein designed to antagonize TNF-α and IL-17A, pivotal in the pathophysiology of autoimmune and inflammatory diseases. Our initial efforts focused on screening for optimal structure by analyzing expression levels, purity, and binding capabilities. The binding affinity of KYS202004A to TNF-α and IL-17A was evaluated using SPR. In vitro, we assessed the inhibitory capacity of KYS202004A on cytokine-induced CXCL1 expression in HT29 cells. In vivo, its efficacy was tested using a Collagen-Induced Arthritis (CIA) model in transgenic human-IL-17A mice and an imiquimod-induced psoriasis model in cynomolgus monkeys. KYS202004A demonstrated significant inhibition of IL-17A and TNF-α signaling pathways, outperforming the efficacy of monotherapeutic agents ixekizumab and etanercept in reducing CXCL1 expression in vitro and ameliorating disease markers in vivo. In the CIA model, KYS202004A significantly reduced clinical symptoms, joint destruction, and serum IL-6 concentrations. The psoriasis model revealed that KYS202004A, particularly at a 2  mg/kg dose, was as effective as the combination of ixekizumab and etanercept. This discovery represents a significant advancement in treating autoimmune and inflammatory diseases, offering a dual-targeted therapeutic approach with enhanced efficacy over current monotherapies.

The efficacy of ixekizumab treatment in Chinese psoriasis patients: a short-term retrospective study.

Ixekizumab is a monoclonal antibody targeting interleukin-17A that has shown significant improvement in alleviating psoriasis. However, data is sparse on the efficacy of ixekizumab in psoriasis patients in China. To investigate the efficacy of ixekizumab in Chinese psoriasis patients. Patients with moderate-to-severe psoriasis were retrospectively investigated from April 2020 to October 2020. A total of 16 patients were treated with 80 mg ixekizumab every two weeks after a 160-mg loading dose. Efficacy was assessed using the Psoriasis Activity and Severity Index (PASI), static Physician's Global Assessment (sPGA) and Dermatology Life Quality Index (DLQI) at Weeks 0, 1, 2, 3, 4, 8, and 12. All patients showed excellent response to the treatment. Compared to baseline level, the improvement was significant and statistically significant at Week 1, 2, 4, 8 and 12 (p<0.05). Of the patients, 18.75% reported sPGA 0/1 (clear or almost clear skin) as early as Week 2, and the percentage of patients who reported sPGA 0/1 reached 100% at Week 12. Moreover, the DLQI decreased gradually coinciding with improvement in PASI and sPGA. The head/neck regions showed the fastest improvements, followed by the trunk and the arms/legs. During the 12-week period, no serious adverse effects occurred. Our results indicate that the treatment of ixekizumab was safe and effective in psoriasis patients in China.

Synthetic BSA-conjugated disaccharide related to the Streptococcus pneumoniae serotype 3 capsular polysaccharide increases IL-17A Levels, γδ T cells, and B1 cells in mice.

The disaccharide (ß-D-glucopyranosyluronic acid)-(1→4)-ß-D-glucopyranoside represents a repeating unit of the capsular polysaccharide of Streptococcus pneumoniae serotype 3. A conjugate of the disaccharide with BSA (di-BSA conjugate) adjuvanted with aluminum hydroxide induced - in contrast to the non-adjuvanted conjugate - IgG1 antibody production and protected mice against S. pneumoniae serotype 3 infection after intraperitoneal prime-boost immunization. Adjuvanted and non-adjuvanted conjugates induced production of Th1 (IFNγ, TNFα); Th2 (IL-5, IL-13); Th17 (IL-17A), Th1/Th17 (IL-22), and Th2/Th17 cytokines (IL-21) after immunization. The concentration of cytokines in mice sera was higher in response to the adjuvanted conjugate, with the highest level of IL-17A production after the prime and boost immunizations. In contrast, the non-adjuvanted conjugate elicited only weak production of IL-17A, which gradually decreased after the second immunization. After boost immunization of mice with the adjuvanted di-BSA conjugate, there was a significant increase in the number of CD45+/CD19+ B cells, TCR+ γδ T cell, CD5+ В1 cells, and activated cells with MHC II+ expression in the spleens of the mice. IL-17A, TCR+ γδ T cells, and CD5+ В1 cells play a crucial role in preventing pneumococcal infection, but can also contribute to autoimmune diseases. Immunization with the adjuvanted and non-adjuvanted di-BSA conjugate did not elicit autoantibodies against double-stranded DNA targeting cell nuclei in mice. Thus, the molecular and cellular markers associated with antibody production and protective activity in response to immunization with the di-BSA conjugate adjuvanted with aluminum hydroxide are IL-17A, TCR+ γδ T cells, and CD5+ В1 cells against the background of increasing MHC II+ expression.

Regulation of Inflammatory Responses of Cow Mammary Epithelial Cells through MAPK Signaling Pathways of IL-17A Cytokines.

The aim of this study is to explore the mechanism of IL-17A infection in the development of bacterial mastitis in dairy cows. In this study, RT-qPCR and ELISA were used to measure the promoting effect of IL-17A on the generation of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and chemokine (IL-8). In addition, Western blot (WB) was applied to measure the influences of IL-17A on the inflammation-related ERK and p38 proteins in the MAPK pathways. The results show that under the stimulation of LPS on cow mammary epithelial cells (CMECs), cytokines IL-1ß, IL-6, IL-8, TNF-α, and IL-17A will exhibit significantly increased expression levels (p < 0.05). With inhibited endogenous expression of IL-17A, cytokines IL-1ß, IL-6, IL-8, and TNF-α will present reduced genetic expression (p < 0.01), with reduced phosphorylation levels of ERK and p38 proteins in the MAPK signaling pathways (p < 0.001). Upon the exogenous addition of the IL-17A cytokine, the genetic expression of cytokines IL-1ß, IL-6, IL-8, and TNF-α will increase (p < 0.05), with increased phosphorylation levels of the ERK and p38 proteins in the MAPK signaling pathways (p < 0.001). These results indicate that under the stimulation of CMECs with LPS, IL-17A can be expressed together with relevant inflammatory cytokines. Meanwhile, the inflammatory responses of mammary epithelial cells are directly proportional to the expression levels of IL-17A inhibited alone or exogenously added. In summary, this study shows that IL-17A could be used as an important indicator for assessing the bacterial infections of mammary glands, indicating that IL-17A could be regarded as one potential therapeutic target for mastitis.

IL-17A-induced cancer-associated fibroblasts releases CXCL12 to promote lung adenocarcinoma progression via Wnt/ß-Catenin signaling pathway.

BACKGROUND: Cancer-associated fibroblasts (CAFs) and their secretion, C-X-C motif chemokine ligand 12 (CXCL12), play an important role in the development of lung adenocarcinoma (LUAD). Interleukin 17A (IL-17A) is also crucial in regulating tumor progression. Herein, we explored the specific relationships between these two factors and their mechanisms in the progression of LUAD. METHODS: Immunohistochemistry was utilized to assess the differential expression levels of IL-17A and CXCL12 in tumor versus normal tissues of LUAD patients, followed by gene correlation analysis. Cell counting kit-8 (CCK8), wound-healing and transwell assays were performed to investigate the effect of IL-17A on the function of LUAD cells. qPCR, immunofluorescence, immunohistochemistry and western blot analyses were conducted to elucidate the potential mechanism by which IL-17A facilitates the development of LUAD via CXCL12. Male BALB-C nude mice were used to explore the role of IL-17A in subcutaneous LUAD mouse models. RESULTS: Elevated expression levels of IL-17A and CXCL12 were observed in LUAD tissues, exhibiting a positive correlation. Further studies revealed that IL-17A could stimulate CAFs to enhance the release of CXCL12, thereby facilitating the growth, proliferation, and metastasis of LUAD. The binding of CXCL12 to its specific receptor influences the activation of the Wnt/ß-Catenin pathway, which in turn affects the progression of LUAD. In vivo experiments have demonstrated that IL-17A enhances the growth of LUAD tumors by facilitating the secretion of CXCL12. Conversely, inhibiting CXCL12 has been demonstrated to impede tumor growth. CONCLUSIONS: We discovered that IL-17A promotes the release of CAFs-derived CXCL12, which in turn facilitates the development of LUAD via the Wnt/ß-Catenin signaling pathway.

[Current treatment for spondyloarthritis: focus on netakimab. A review].

Spondyloarthritis (SpA) is a group of rheumatic diseases that includes ankylosing spondylitis (AS), psoriatic arthritis (PsA) and a number of other diseases. SpA lead to a significant social problem, since it is a common pathology that debuts mainly at a young age, significantly impairing the ability to work and the ability to social contacts of the most active part of the population. For all the main types of chronic progressive SpA, biological agents (biologics) are of great importance in patients with persistent activity despite standard treatment, especially in the case of predominantly axial involvement, since in this case it is actually the only option for effective treatment, in addition to the constant use of non-steroidal anti-inflammatory drugs (NSAIDs). Over the past decade, interleukin-17A (IL-17A) inhibitors have taken the first place in therapy of SpA, because, according to modern ideas about pathogenesis, IL-17A may be a key target for therapeutic intervention in SpA. In terms of ensuring availability for Russian patients with SpA, it is of particular importance to the introduction of the original medication from the group of IL-17A inhibitors Netakimab (NTK). This review presents data from randomized clinical trials of NTK phases I, II and III in AS and PsA also post-registration observational studies of phase IV, including analysis of subpopulations of patients of special interest, in particular, patients with psoriatic spondylitis. NTK demonstrated high effectiveness in the treatment of SpA both in randomized clinical trials and in clinical practice. The drug is characterized by a rapid onset of clinical action and persistent maintenance of the achieved improvement, a complex effect on various manifestations of the disease, is able to have a structure-modifying effect and slow down the progression of both the erosive process and osteoproliferation. The safety profile of NTK is generally typical for the entire group of IL-17 inhibitors. The drug has low immunogenicity, which allows us to count on the possibility of many years of effective use. Resolutions of expert councils on the use of NTK in AS and PsA support the inclusion of this drug in clinical guidelines.

Amiloride lowers plasma TNF and interleukin-6 but not interleukin-17A in patients with hypertension and type 2 diabetes.

Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na+ channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1ß, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: 1) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension (n = 69, amiloride 5-10 mg/day for 8 wk) and 2) patients with hypertension and type 1 diabetes mellitus (T1DM) (n = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K+ increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1ß. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages.NEW & NOTEWORTHY ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.

Interleukin-17A in diabetic retinopathy: The crosstalk of inflammation and angiogenesis.

Diabetic retinopathy (DR) is a severe ocular complication of diabetes which can leads to irreversible vision loss in its late-stage. Chronic inflammation results from long-term hyperglycemia contributes to the pathogenesis and progression of DR. In recent years, the interleukin-17 (IL-17) family have attracted the interest of researchers. IL-17A is the most widely explored cytokine in IL-17 family, involved in various acute and chronic inflammatory diseases. Growing body of evidence indicate the role of IL-17A in the pathogenesis of DR. However, the pro-inflammatory and pro-angiogenic effect of IL-17A in DR have not hitherto been reviewed. Gaining an understanding of the pro-inflammatory role of IL-17A, and how IL-17A control/impact angiogenesis pathways in the eye will deepen our understanding of how IL-17A contributes to DR pathogenesis. Herein, we aimed to thoroughly review the pro-inflammatory role of IL-17A in DR, with focus in how IL-17A impact inflammation and angiogenesis crosstalk.

IL-17A/IL-17RA interaction blockade sensitizes synovial macrophages to efferocytosis and PD-L1 signaling via rewiring STAT-3/ADAM17/MERTK axis in rheumatoid arthritis animal model.

Defective clearance of apoptotic cells due to impaired efferocytosis sustains error in self-tolerance that exacerbates rheumatoid arthritis (RA). However, the molecular determinant that directly or specifically impairs efferocytosis in RA is not yet studied. We identified a new perspective that IL-17A significantly impedes efferocytosis via preferential activation of the JAK/STAT-3/ADAM17 signaling axis. In contrast, disruption of the IL-17A/IL-17RA interaction using cyanidin or silencing of IL-17RA obstructed JAK/STAT-3 activation that further abolished ADAM17 expression. Subsequent depletion of ADAM17 inhibited the shedding of Mer tyrosine kinase receptor (MERTK), which significantly increased apoptotic cell intake and restored efferocytosis in adjuvant-induced arthritic (AA) model. Concomitantly, the amplification of the efferocytosis process due to IL-17A/IL-17RA interaction disruption was sensitive to mitochondrial fission mediated via Drp-1 phosphorylation downstream of STAT-3 inhibition. As expected, cyanidin treated AA synovial macrophages that exhibited increased efferocytosis demonstrated a phenotypic shift towards CD163 anti-inflammatory phenotype in a STAT-5 dependent manner. Similar results were obtained in IL-17A-sensitized AA synovial macrophages treated with S3I-201 (a STAT-3 inhibitor) indicating that IL-17A influences efferocytosis via the STAT-3 pathway. In view of our previous work where cyanidin restored Th17/Treg balance, our present investigation fulfils a critical gap by providing scientific validation that cyanidin escalated PD-L1 expression during the efferocytosis process that could have impacted the restoration of Th17/Treg balance in an AA model. Together, these data corroborate the hypothesis that IL-17A signaling can impair efferocytosis via regulating STAT-3/ADAM17/FL-MERTK axis and that its inhibition can amplify a pro-resolution signal against RA progression.

Involvement of PD-1+CD4+ T cells in the development of traumatic tracheal stenosis by regulating the IL-17/STAT3 pathway.

Studies have highlighted an upregulation of PD-1 expression in CD4+ T cells, which accelerates lung fibrosis by activating the IL-17/STAT3 pathway, leading to IL-17A and TGF-ß1 secretion. However, the relation with traumatic tracheal stenosis (TS) remains unexplored. Our analysis found significant increases in PD-1+CD4+ T cells, IL-17A, and TGF-ß1 in the TS patients (n = 10). The cellular model used CD4+ T cells co-cultured with bronchial fibroblasts while the animal model used a nylon brush to scrape the damaged tracheal mucosa. Interventions with PD-1 and STAT3 inhibitors both in vitro (n = 5) and in vivo (n = 6) showed decreased expression of TGF-ß1 and IL-17A in CD4+ T cells, decreased collagen I synthesis in vitro, and reduced tractal fibrosis in vivo. Furthermore, PD-1's modulation of the STAT3 was evident. This research unveils PD-1+CD4+ T cells' role in TS, thus suggesting a novel immunotherapeutic strategy to counteract tracheal fibrosis.

Salivary interleukin-17A and interleukin-18 levels in patients with celiac disease and periodontitis.

Background: An increased level of interleukin-17A and interleukin-18 in the serum and intestinal mucosa of celiac disease patients reflecting the severity of villous atrophy and inflammation was documented. Thus, the objective of this study was to evaluate the concentrations of salivary-17A, interleukin-1 beta, and interleukin-18 in patients with celiac disease who are on a gluten-free diet, both with and without periodontitis, and to compare these levels with those in healthy individuals. Methods: The study involved 23 participants with serologically confirmed celiac disease (CD) and 23 control subjects. The CD patients had been following a gluten-free diet (GFD) for a minimum of 1 year and had no other autoimmune disorders. The research involved collecting demographic data, conducting periodontal examinations, gathering unstimulated whole saliva, and performing enzyme-linked immunosorbent assays to measure salivary interleukin-17A, interleukin-1 beta, and interleukin-18 levels. Spearman's correlation analysis was utilized to explore the relationships between CD markers in patients on a GFD and their periodontal clinical findings. Results: The periodontal findings indicated significantly lower values in celiac disease patients adhering to a gluten-free diet compared to control subjects (p = 0.001). No significant differences were found in salivary IL-17A, IL-18, and IL-1B levels between celiac disease patients and control subjects. Nevertheless, the levels of all interleukins were elevated in periodontitis patients in both the celiac and control groups. The IL-1 Beta level was significantly higher in periodontitis patients compared to non-periodontitis patients in the control group (p = 0.035). Significant negative correlations were observed between serum IgA levels and plaque index (r = -0.460, p = 0.010), as well as gingival index (r = -0.396, p = 0.030) in CD patients on a gluten-free diet. Conclusion: Celiac disease patients on gluten-free diet exhibited better periodontal health compared to control subjects. However, increased levels of salivary IL-17A, IL-18 and IL-1B levels were associated with periodontitis. Additionally, serum IgA level was significantly inversely associated with periodontitis clinical manifestations and with salivary inflammatory mediators in CD patients on GFD.

Genetic association of Interleukin-17A polymorphism in Bangladeshi patients with breast and cervical cancer: a case-control study with functional analysis.

BACKGROUND: Breast and cervical cancer are the two leading cancers in terms of incidence and mortality. Previous studies reported different interleukins, including interleukin-17A (IL-17A) to be responsible for the development and progression of these malignancies. Therefore, we speculated that the variants in this gene might be associated with these cancer developments in Bangladeshi population. For evaluating the hypothesis, we investigated the association of IL-17A rs3748067 polymorphism with the susceptibility of both breast and cervical cancer. METHODS: This case-control study was performed on 156 breast cancer patients, 156 cervical cancer patients, and 156 controls using the tetra-primer amplification refractory mutation system-polymerase chain reaction. The statistical software package SPSS (version 25.0) was applied for analyses. The genetic association was measured by the odds ratio (OR) and 95% confidence intervals (CIs). A statistically significant association was considered when p-value ≤ 0.05. Functional analysis was performed using GEPIA and UALCAN databases. RESULTS: From the calculation of the association of IL-17A rs3748067 with breast cancer, it is found that no genotype or allele showed a statistically significant association (p>0.05). On the other hand, the analysis of IL-17A rs3748067 with cervical cancer demonstrated that CT genotype showed a significant association (CT vs. CC: OR=1.79, p=0.021). In the overdominant model, CT genotype also revealed a statistically significant association with cervical cancer, which is found to be statistically significant (OR=1.84, p=0.015). CONCLUSION: Our study summarizes that rs3748067 polymorphism in the IL-17A gene may be associated with cervical cancer but not breast cancer in Bangladeshi patients. However, we suggest studies in the future with a larger sample size.

An evaluation of secukinumab for the treatment of moderate-to-severe hidradenitis suppurativa.

INTRODUCTION: Until recently, biological therapy for hidradenitis suppurativa was limited to anti-tumor necrosis factor (TNF) blockade with adalimumab (ADA). However, not all patients respond to treatment with ADA. This highlighted the need for more therapeutic options. Interleukin (IL)-17/T-helper 17 (Th17) axis may play an important role in the pathophysiology of HS. Recently, the IL-17A inhibitor secukinumab, which targets IL-17A specifically and prevents it from interacting with the IL-17 receptor, has been FDA-approved for HS. AREAS COVERED: Secukinumab, represents a novel therapeutic strategy in HS management. An overview of structural and pharmacological characteristics is provided. Described efficacy in clinical trials and case reports and safety data from is presented. EXPERT OPINION: As response to anti-TNFas is lost over time, secukinumab has provided an alternative HS treatment option in clinical practice. Overall, secukinumab has shown good efficacy and a favorable side effect profile in HS clinical trials but may be avoided in patients with inflammatory bowel disease. Long-term and real-life data on the use of secukinumab are essential for improving decision-making in HS therapy.

Haematopoietic innate interleukin 17A production drives immunopathology in female mouse genital Chlamydia muridarum infection.

Chlamydia trachomatis infection is the leading cause of bacterial urogenital infection and has been demonstrated to drive inflammation and scarring of the reproductive tract. Recent studies have identified key triggers of proinflammatory adaptive immune responses driven by innate leukocytes and epithelia driving immunopathology. Utilizing chimeric mouse models, we investigated the definitive source and role of IL17 and IL17 signalling receptors during early Chlamydia muridarum infection of the female urogenital tract. Bone marrow transplants from wild-type (WT) and IL17A-/- mice to recipients demonstrated equivocal infection kinetics in the reproductive tract, but interestingly, adoptive transfer of IL17A-/- immune cells to WT recipients resulted in no infertility, suggesting a haematopoietic (as opposed to tissue) source of IL17 driving immunopathology. To further delineate the role of IL17 in immunopathology, we infected WT and IL17 receptor A (IL17RA)-/- female mice and observed a significant reduction in immunopathology in IL17RA-/- mice. WT bone marrow transplants to IL17RA-/- recipient mice prevented hydrosalpinx, suggesting signalling through IL17RA drives immunopathology. Furthermore, early chemical inhibition of IL17 signalling significantly reduced hydrosalpinx, suggesting IL17 acts as an innate driver of disease. Early during the infection, IL17 was produced by γδ T cells in the cervico-vagina, but more importantly, by neutrophils at the site of infertility in the oviducts. Taken together, these data suggest innate production of IL17 by haematopoietic leukocytes drives immunopathology in the epithelia during early C. muridarum infection of the female reproductive tract.

An externally validated clinical-laboratory nomogram for myocardial involvement in adult idiopathic-inflammatory-myopathy patients.

OBJECTIVES: This study aimed at identifying clinical and laboratory risk factors for myocardial involvement (MI) in idiopathic inflammatory myopathies (IIMs) patients as well as constructing a risk-predicted nomogram for prediction and early identification of MI. METHODS: An IIMs cohort in southeastern China was constructed, including 504 adult IIMs patients who met the inclusion and exclusion criteria, and were hospitalized at four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine from January 1st 2018 to April 30st 2022. After dividing patients into the training cohort and the validation cohort, risk factors for MI were identified through least absolute shrinkage and selection operator regression and multivariate logistic regression. A risk-predicted nomogram was established and validated internally and externally for discrimination, calibration and practicability. RESULTS: In this cohort, 17.7% of patients developed MI and the survival was significantly inferior to that of IIMs patients without MI (P < 0.001). In the training cohort, age > 55 years old (P < 0.001), disease activity > 10 points (P < 0.001), interleukin-17A (IL-17A) > 7.5 pg/ml (P < 0.001), lactic dehydrogenase (LDH) > 425 U/L (P < 0.001), anti-mitochondrial antibodies (AMAs, P = 0.017), and anti-MDA5 antibody (P = 0.037) were significantly correlated with development of MI. A nomogram was established by including the above values to predict MI and was found efficient in discrimination, calibration, and practicability through internal and external validation. CONCLUSION: This study developed and validated a nomogram model to predict the risk of MI in adult IIMs patients, which can benefit the prediction and early identification of MI as well as timely intervention in these patients.

Alnustone promotes megakaryocyte differentiation and platelet production via the interleukin-17A/interleukin-17A receptor/Src/RAC1/MEK/ERK signaling pathway.

OBJECTIVES: Thrombocytopenia is a disease in which the number of platelets in the peripheral blood decreases. It can be caused by multiple genetic factors, and numerous challenges are associated with its treatment. In this study, the effects of alnustone on megakaryocytes and platelets were investigated, with the aim of developing a new therapeutic approach for thrombocytopenia. METHODS: Random forest algorithm was used to establish a drug screening model, and alnustone was identified as a natural active compound that could promote megakaryocyte differentiation. The effect of alnustone on megakaryocyte activity was determined using cell counting kit-8. The effect of alnustone on megakaryocyte differentiation was determined using flow cytometry, Giemsa staining, and phalloidin staining. A mouse model of thrombocytopenia was established by exposing mice to X-rays at 4 Gy and was used to test the bioactivity of alnustone in vivo. The effect of alnustone on platelet production was determined using zebrafish. Network pharmacology was used to predict targets and signaling pathways. Western blotting and immunofluorescence staining determined the expression levels of proteins. RESULTS: Alnustone promoted the differentiation and maturation of megakaryocytes in vitro and restored platelet production in thrombocytopenic mice and zebrafish. Network pharmacology and western blotting showed that alnustone promoted the expression of interleukin-17A and enhanced its interaction with its receptor, and thereby regulated downstream MEK/ERK signaling and promoted megakaryocyte differentiation. CONCLUSIONS: Alnustone can promote megakaryocyte differentiation and platelet production via the interleukin-17A/interleukin-17A receptor/Src/RAC1/MEK/ERK signaling pathway and thus provides a new therapeutic strategy for the treatment of thrombocytopenia.

Vitamin D Deficiency Participates in Depression of Patients with Diabetic Peripheral Neuropathy by Regulating the Expression of Pro-Inflammatory Cytokines.

Objective: Vitamin D deficiency is associated with patients with diabetic peripheral neuropathy (DPN), and low levels of vitamin D are common in patients with depression. Depression is common in DPN patients and the definite pathogenesis remains unclear. This study aimed to determine vitamin D deficiency in the onset of depression in DPN and evaluate the effect of vitamin D supplementation on depression. Methods: A total of 192 patients with DPN were enrolled in this study. Clinical and laboratory information was collected. Chemiluminescent immunoassay was used to measure the level of 25(OH)D. Enzyme-linked immunosorbent assay was employed to measure the concentrations of interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), and IL-17A. Subjects with low 25(OH)D received 5000IU vitamin D daily for 12 weeks. Depression scores and levels of 25(OH)D, IL-1ß, TNF-α, and IL-17A were re-evaluated after supplementation. Results: The incidence of vitamin D deficiency and depression was high in DPN patients. Compared with vitamin D sufficient participants, Hamilton Depression Rating Scale (HAMD) scores and the levels of inflammatory markers IL-1ß, TNF-α, and IL-17A were significantly higher in insufficient group (all p<0.05). HAMD score, IL-1ß, TNF-α, and IL-17A were negatively correlated with 25(OH)D (all p<0.05). A linear relationship existed among IL-1ß, TNF-α, IL-17A, and 25(OH)D (p<0.05). HAMD scores, IL-1ß, TNF-α, and IL-17A were all reduced significantly after supplementation of vitamin D (p<0.05). Binary logistic analysis revealed that vitamin D insufficiency was an independent risk factor for depression in patients with DPN. Receiver operating characteristic (ROC) curve analysis showed a high sensitivity (87.20%) of 25(OH)D in discriminating DPN patients with depression. Conclusion: Vitamin D deficiency participated in occurrence of depression in DPN patients and could be mediated, at least in part, by upregulation of pro-inflammatory cytokines. Vitamin D supplementation may be effective in improving depressive symptoms in DPN patients.

Interleukin-17A Inhibitors in Patients with Psoriasis and Tuberculosis Infection: A 2-Year Prospective Study on Safety Without Preventive Treatment.

INTRODUCTION: The necessity for tuberculosis preventive treatment (TPT) and routine T-SPOT.TB monitoring in patients with psoriasis and tuberculosis infection (TBI) undergoing interleukin (IL)-17A inhibitor therapy remains uncertain. This study aims to evaluate the long-term safety of IL-17A inhibitors administered without TPT and analyze changes in T-SPOT.TB among these patients. It also identifies risk factors for TBI in patients with psoriasis. METHODS: This single-center prospective study enrolled adult patients with plaque psoriasis and TBI receiving IL-17A inhibitors. TBI was defined as positive T-SPOT.TB results (≥ 6 spots) without symptoms or evidence of active tuberculosis (ATB). TPT administration was based on contraindications, tuberculosis risk factors, and patient preferences. The primary endpoint was the incidence of ATB over 2 years. Secondary outcomes included T-SPOT.TB changes and TBI risk factors. RESULTS: Of the 129 patients with psoriasis and TBI enrolled in the study, 97 (75.2%) did not receive TPT, while 32 (24.8%) did. Among them, 109 patients (84.5%) completed the 2-year follow-up. During the 235 person-years of observation, no ATB cases were identified. Median T-SPOT.TB values showed no significant changes from baseline to year 2 in both the non-TPT (20 vs. 17 spots, p = 0.975) and TPT groups (55 vs. 58 spots, p = 0.830). T-SPOT.TB reversed in 14 patients (12.8%), mostly in the non-TPT group. Moreover, for TBI risk factor analysis, a cohort of 212 patients with psoriasis with negative baseline T-SPOT.TB was evaluated, revealing a TBI prevalence of 37.8%. Logistic regression analysis highlighted age ≥ 45 years (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.50-3.99, p < 0.001) and body mass index (BMI) < 24.0 kg/m2 (OR 2.12, 95% CI 1.27-3.54, p = 0.004) as independent risk factors for TBI. CONCLUSION: IL-17A inhibitors do not appear to reactivate tuberculosis in patients with psoriasis and TBI, potentially reducing the need for routine TBI screening and preventive treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100045823.