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Sepsis represents a syndrome of systemic inflammatory response, which is mostly a result of infection with various pathogenic microorganisms, characterized by an uncontrolled infection response of the organism leading to life-threatening organ dysfunction. Long noncoding RNA (lncRNA), as competing endogenous RNA, can affect the binding of microRNA (miRNA) to mRNA, thus influencing the development of sepsis. In this study, based on transcriptome data from GEO database, we screened differentially expressed lncRNAs and constructed lncRNA-miRNA-mRNA network. And pathway IL-17RA-1/miR-7847-3p/protein kinase C gamma (PRKCG) coexpression network was successfully sorted out. The effect of this network on LPS-induced sepsis model in THP-1 cells was also verified by CCK-8, scratch, ELISA, Western blot, and qRT-PCR assays. Corresponding binding sites of miR-7847-3p to IL-17RA-1 and miR-7847-3p to PRKCG were verified using dual luciferase gene reporter assays, respectively. Compared with control, si-IL-17RA-1 significantly inhibited the cell viability and migration ability of THP-1, and levels of proinflammatory factors IL-6, IL-1β, and TNF-α secreted were markedly decreased, and the expression of IL-17RA-1, PRKCG, p-MEKK1, and p-JNK were markedly reduced. In addition, IL-17RA-1 could target binding to miR-7847-3p and inhibit its expression, and miR-7847-3p could also bind to PRKCG. Our experiments demonstrate that IL17-RA-1 attenuates the sepsis response through the miR-7847-3p/MAPK pathway, and this competing endogenous RNA (ceRNA) network may be a potential approach to predict and combat sepsis.

Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of

BARD1 is a tumor suppressor that is necessary for the functioning and stability of BRCA1, with which it forms a heterodimer and participates in the repair of DNA double-strand breaks. The cellular level of BARD1 and its interaction with BRCA1 are crucial for BRCA1/BARD1 function in homologous recombination and tumor suppression. However, the regulatory mechanism underpinning the stability of BARD1 is largely unclear. In this study, we identified DCAF8L2, a DDB1-Cullin associated factor (DCAF) associated with CRL4 E3 ligase, as a negative regulator of BARD1. Mechanistically, DCAF8L2 interacts with and targets BARD1 for ubiquitination and degradation. In addition, the interaction of DCAF8L2 with BARD1 through the RING domain could compete with the dimerization of BRCA1 and BARD1, leading to increased cellular uncoupling of BARD1 and BRCA1, subjecting the latter to degradation. The overexpression of DCAF8L2 compromises the homologous recombination process and confers cells with increased sensitivity to DNA damage. Furthermore, DCAF8L2 was aberrantly expressed in breast cancer cell lines. Our findings suggest that DCAF8L2 may play an oncogenic role in the pathogenesis of breast cancer, possibly by negative regulation of BARD1.

Background Interleukin (IL)-17A has a dual role in tumor immunity, promotes anti-tumor responses and facilitates angiogenesis by interacting with IL-17 receptor A (IL-17RA). Although IL-17A has been associated with the pathogenesis of papillary thyroid carcinoma (PTC), the nucleotide variability at the IL17A and IL17RA genes is still poorly characterized. Aim To assess the contribution of the IL17A (-197 G >A, rs2275913) and IL17RA (-947 A >G, rs4819554) single nucleotide polymorphisms (SNP) on the development and progression of PTC and on IL-17 plasma levels. Methods We studied 188 PTC patients and 170 healthy controls. SNPs were identified using PCR-amplified DNA and restriction fragment length polymorphism (RFLP) techniques. Plasma levels of IL-17A was evaluated in 83 PTC patients using ELISA. Statistical analyses were performed to evaluate the associations between SNPs and clinicohistopathological features of PTC and IL-17A levels. Results No significant difference was observed regarding the allele and genotype distributions of both SNPs between PTC patients and controls. The IL17A GA was associated with poor biochemical and structural incomplete response to therapy, whereas no influence over the IL-17A expression was observed. The IL17RA AG was significantly associated with small-sized tumors, initial tumor stage at diagnosis and better response to therapy. Conclusions The IL17A SNP may predict an aggressive manifestation of PTC, whereas the IL17RA SNP was associated with a more favorable clinical outcome.

BRCA1 is frequently down-regulated in breast cancer, the underlying mechanism is unclear. Here we identified DCAF8L1, an X-linked gene product, as a DDB1-Cullin associated Factor (DCAF) for CUL4 E3 ligases to target BRCA1 and BARD1 for proteasomal degradation. Forced expression of DCAF8L1 caused reduction of BRCA1 and BARD1, and impaired DNA damage repair function, conferring increased sensitivity to irradiation and DNA damaging agents, as well as Olaparib, a PARPi anticancer drug; while depletion of DCAF8L1 restored BRCA1 and suppressed the growth of its xenograft tumors. Furthermore, the expression of DCAF8L1 was induced in human H9 ES cells during transition from primed to naïve state when Xi chromosome was reactivated. Aberrant expression of DCAF8L1 was observed in human breast fibroadenoma and breast cancer. These findings suggest that CRL4

The interaction between interleukin-17A (IL-17A) and IL-17A receptor (IL-17RA) is a crucial target of psoriasis. Several natural compounds from foods or herbs have displayed efficacies on the amelioration of psoriasis. However, the anti-psoriatic mechanisms are mostly through the common anti-inflammatory effects and rarely

Myocardial ischemia reperfusion (I/R) injury is a complex process with intense inflammatory response and cardiomyocyte apoptosis. As a decoy receptor of IL-1β, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1β signaling. However, its role in I/R injury remains unknown. Here we found that the serum levels of IL-1R2 were significantly increased in patients with acute myocardial infarction (AMI) following interventional therapy. Similarly, after myocardial I/R surgery, IL-1R2 expression was significantly increased in heart of wild-type mice. In addition, IL-1R2-deficient mice heart showed enlarged infarct size, increased cardiomyocyte apoptosis together with reduced cardiac systolic function. Following exposure to hypoxia and reoxygenation (H/R), neonatal rat ventricular myocytes (NRVM) significantly increased IL-1R2 expression relying on NF-κB activation. Consistently, IL-1R2-deficient mice increased immune cells infiltrating into heart after surgery, which was relevant with cardiac damage. Additionally, IL-1R2 overexpression in cardiomyocyte protected cardiomyocyte against apoptosis through reducing the IL-17RA expression both in vivo and in vitro. Our results indicate that IL-1R2 protects cardiomyocytes from apoptosis, which provides a therapeutic approach to turn down myocardial I/R injury.

Interleukin-17 (IL-17) is a family of pro-inflammatory cytokines and has been involved in the pathogenesis of chronic inflammatory and autoimmune diseases. The IL-17E, also known as IL-25, is a distinct member of this family that binds to its unique receptor IL-17Rb to induce the activation of nuclear factor kappa-light-chain enhancer of activated B cells. Here, we systematically examined the intermolecular recognition and association of IL-25 with IL-17Rb and demonstrated that the IL-25 primarily adopts two discrete linear and cyclic epitopes to interact with IL-17Rb. The two epitopes are separately located in the monomers 1 and 2 of IL-25 homodimer and cover sequences

BACKGROUND: IL-17A–producing CD4(+) T helper (T(H)17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD4(+) T cell subsets, remains to be elucidated. METHODS: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4(+) T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated T(H)17 cell–specific IL-17RA and IL-17RC gene–deficient mice and studied the functional role of IL-17 signaling in T(H)17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4(+)CD45RB(high) T cell transfer colitis model. RESULTS: We identified a specific expression of the IL-17 receptor A/C complex on CD4(+) T(H)17 cells. Single-cell RNA sequencing of T(H)17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4(+) T cells and, most importantly, specifically in CD4(+) T(H)17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. CONCLUSIONS: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4(+) T(H)17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T(H)17 treatment strategies.

Background: To evaluate the effect of T-helper 17 (Th17) cells and Th9 cells on the activation of dermal vascular smooth muscle cells (DVSMCs) in systemic scleroderma (SSc) and regulation of tanshinone IIA. Methods: The expression of interleukin 17 receptor (IL-17R) and interleukin 9 receptor (IL-9R) in the skin of SSc patients was assessed by immunofluorescence. The expression of IL-9 and IL-9R mRNA in peripheral blood mononuclear cells (PBMCs) of SSc patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The proportion of Th9 cells in PBMCs of SSc patients was sorted by flow cytometry. The effect of IL-9 on the differentiation of Th17 and IL-17 on that of Th9 was detected by flow cytometry. The proportion of Th9 and Th17 cells in SSc patients was detected by flow cytometry. The level of collagen I, III, α-SMA, IL-9R, IL-17R, JNK, P38, and ERK were analyzed using western blot (WB). Results: Th9 cells were highly expressed in SSc. IL-9 stimulated the differentiation of immature T cells into Th17 cells. IL-17 induced the differentiation of immature T cells intoTh9 cells. Tanshinone IIA inhibited the differentiation of immature T lymphocytes into Th17 and Th9. WB showed that the combined action of IL-17 and IL-9 upregulated the inflammation and proliferation of DVSMCs. Anti-IL17, anti-IL9, and tanshinone IIA inhibited the functional activation of DVSMCs. Study limitations: For Th17, Th9 and vascular smooth muscle cells, the study on the signal pathway of their interaction is not thorough enough. More detailed studies are needed to explore the mechanism of cell-cell interaction. Conclusions: The current results suggested that Th17 and Th9 cells induced the activation of DVSMCs in SSc through crosstalk in vitro, and tanshinone IIA inhibited the process.

Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell‐derived factors such as cytokines and chemokines plays a central role. IL‐25, as a member of the IL‐17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL‐25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL‐25 exerts a tumor‐suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor‐supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type‐2 immune responses. Since IL‐25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL‐25‐based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL‐25 has a tumor‐suppressive function, employing IL‐25‐enhancing approaches, such as Virulizin® and dihydrobenzofuran administration, has potentially inhibited tumor cell growth. On the other hand, in the case of IL‐25‐dependent tumor progression, using IL‐25 blocking methods, including anti‐IL‐25 antibodies, might be a complementary approach to the other anticancer agent. Collectively, it is hoped, IL‐25 might be a promising target in cancer treatment., This study is focused on the role of IL‐25 in cancer development. It has been shown that IL‐25 exerts conflicting functions in the tumor microenvironment. Using IL‐25‐based therapies might introduce novel approaches in cancer treatment.

Ependymal cells have been suggested to act as neural stem cells and exert beneficial effects after spinal cord injury (SCI). However, the molecular mechanism underlying ependymal cell regulation after SCI remains unknown. To examine the possible effect of IL-17A on ependymal cell proliferation after SCI, we locally administrated IL-17A neutralizing antibody to the injured spinal cord of a contusion SCI mouse model, and revealed that IL-17A neutralization promoted ependymal cell proliferation, which was paralleled by functional recovery and axonal reorganization of both the corticospinal tract and the raphespinal tract. Further, to test whether ependymal cell-specific manipulation of IL-17A signaling is enough to affect the outcomes of SCI, we generated ependymal cell-specific conditional IL-17RA-knockout mice and analyzed their anatomical and functional response to SCI. As a result, conditional knockout of IL-17RA in ependymal cells enhanced both axonal growth and functional recovery, accompanied by an increase in mRNA expression of neurotrophic factors. Thus, Ependymal cells may enhance the regenerative process partially by secreting neurotrophic factors, and IL-17A stimulation negatively regulates this beneficial effect. Molecular manipulation of ependymal cells might be a viable strategy for improving functional recovery.

Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.

Pancreatic cancer is a common malignant tumor with poor prognosis. Recently, cancer stem cells (CSCs) were identified in several solid tumors, including pancreatic cancer. Although accumulating evidence indicates that sirtuin 1 (SIRT1) exerts biological functions in various cancers, how it contributes to tumorigenesis and metastasis of pancreatic cancer, as well as its role in CSCs, is still poorly defined. Here we show that SIRT1 interacts with the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex, which is responsible for H2AK119 monoubiquitination (H2AK119ub1), collaborating as a functional unit. Genome-wide analysis of SIRT1/CUL4B targets identified a cohort of genes, including GRHL3 and FOXO3, critically involved in cell differentiation, growth, and migration. Furthermore, we found that SIRT1 and CUL4B collectively promote the proliferation, autophagy, and invasion of pancreatic cancer cells. Remarkably, we demonstrate that SIRT1/CUL4B promotes CSC-like properties, including increased stemness marker expression and sphere formation. In vivo experiments implied that SIRT1 promoted established tumor xenograft growth, increased tumor-initiating capacity in NOD/SCID mice, and increased CSC frequency. Strikingly, SIRT1 and CUL4B expression is markedly upregulated in a variety of human cancers, including pancreatic cancer. Our data provide a molecular basis for the functional interplay between histone deacetylation and ubiquitination. The results also implicate the SIRT1/CRL4B complex in pancreatic cancer metastasis and stem cell properties, thus supporting SIRT1 as a promising potential target for cancer therapy development.

OBJECTIVE Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta-analysis of genome-wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. METHODS In an ethnicity/indication-specific, trans-ethnic, trans-population meta-analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long-term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. RESULTS In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10-8 ), including a single-nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans-ethnic, trans-population meta-analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta-analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta-analysis hazard ratio 3.6 [95% confidence interval 2.40-5.44], P = 7.6 × 10-10 ; frequency of risk allele ~12% in East Asian subjects versus

Present study has been carried out to analyze the IL-17R gene expression in PBMCs of patients with premature coronary artery disease (CAD) in comparison to normal controls.Premature CAD results in disability and lack of quality of life over the years and consequent mortality. Cardiovascular disease (CVD) has global distribution. In 2022, CAD is the leading cause of mortality in the United States and Iran. IL-17 cytokine family plays an important role in promoting inflammation and producing pro-inflammatory cytokines, chemokines, and matrix metalloproteinases.Entirely, 60 subjects were entered into this examination. The case group consisted of 30 subjects with CAD as well as the control group which consisted of 30 healthy persons. The real-time quantitative reverse transcription PCR assay was used to find out, the relative expression (fold) level of IL-17R gene.Our findings indicated that, the relative expression (fold) level of IL-17R gene in the patients group showed an increased level as compared to the control group. The analysis of findingsobtained in this study showed that the patient group is significantly different from the control group regarding the IL-17R mRNA level (fold) (p = 0.035).It has been concluded that IL-17R plays an important role in the pathogenesis of CAD. It follows that superior understanding of IL-17/IL-17R signaling way will be vital for innovating novel therapeutic targets that will facilitate the designing of new drugs for the management of patients (Ref. 40).

Chronic pain remains to be a clinical challenge and is recognized as a major health problem with varying impacts on quality of life. Currently, the first-line therapy for chronic pain is opioids, which are often accompanied by unwanted psychoactive side effects. Thus, new and effective treatments for chronic pain are urgently needed and eagerly pursued. Inflammatory cytokines, especially interleukin-17 (IL-17), are reportedly potential therapeutic targets owing to their pivotal role in chronic pain from the neuroinflammation perspective. Recently, substantial evidence confirmed that IL-17 and IL-17 receptors (IL-17Rs) were increased in neuropathic, inflammatory, and cancer pain models. Notably, IL-17/IL-17R antibodies also reportedly relieve or cure inflammatory- and pain-related diseases. However, existing studies have reported controversial results regarding IL-17/IL-17Rs as potential therapeutic targets in diverse animal models of chronic pain. In this review, we present a summary of published studies and discuss the evidence, from basic to clinical to research, regarding the role and mechanism of action between IL-17 and diverse kinds of chronic pain in animal models and clinical patients. Furthermore, we evaluated IL-17-based therapy as a potential therapeutic strategy for inflammatory- and pain-related disease. Importantly, we also discussed clinical trials of IL-17/IL-17R targeting monoclonal antibodies. Overall, we found that IL-17 is a potential therapeutic target for chronic pain from the perspective of neuroinflammation.

Brodalumab, an interleukin-17 receptor A antagonist, is approved for treatment of moderate-to-severe plaque psoriasis in adults without response or with loss of response to other systemic therapies. In the United States, there is a boxed warning for brodalumab regarding suicidal ideation and behavior; however, no causal relationship between brodalumab and suicidality was established during pivotal trials. In the 2-year pharmacovigilance data, no completed suicides or suicide attempts were reported. The most frequent adverse event (AE) was arthralgia. The safety profile of brodalumab is now being updated after 3 years of pharmacovigilance data. Here, we outline pharmacovigilance data reported to Ortho Dermatologics by patients and healthcare professionals in the United States from August 15, 2017, to August 14, 2020. Brodalumab exposure estimates were obtained by calculating the time between first and last prescription-dispensing authorization dates. Data from 1854 patients were collected, and brodalumab exposure was estimated to be 2736 patient-years. The most frequent AE was arthralgia (111 events; 0.04 events per patient-year). One episode of suicide attempt was reported in a patient with a history of depression. No completed suicides were reported. There were 81 serious infections reported, none of which were fungal. Over the 3-year period, 30 malignancies occurred in 25 patients, none of which were determined to be related to brodalumab. Three-year pharmacovigilance data are consistent with the safety profile of brodalumab previously reported in long-term analyses of clinical trials and the 2-year pharmacovigilance data.

INTRODUCTION: Injury compromises our epithelial barriers, leaving them vulnerable to external threats. Organismal survival thus impinges on rapid barrier re-establishment after damage. Immunocompromised individuals and immunodeficient animals have profound defects in epithelial repair. However, the precise mechanisms and consequences of immune-epithelial cross-talk after injury remain incompletely defined. RATIONALE: Epithelial repair requires cellular adaptation to the hypoxic wound microenvironment through evolutionarily conserved hypoxia-inducible factors (HIFs). This response has long been thought to depend upon epithelial cell-autonomous sensing of oxygen deprivation and responsiveness through HIFs. However, whether and how supportive microenvironmental signals from immune cells intersect with ancient hypoxia responses during epithelial repair have yet to be explored. To address these questions, we were drawn to the skin, a primary epithelial barrier that is surveilled by immune cells and has evolved sophisticated repair mechanisms. RESULTS: Using unbiased profiling of repair-associated lymphocytes, we uncovered the enrichment of heterogeneous populations of type 17 lymphocytes. Homozygous Rorgt-EGFP (GFI-KI) mice deficient in RORγt(+) cells exhibited a significant defect in epithelial migration and wound re-epithelialization. After damage, we observed a rapid local expansion of preexisting skin-resident RORγt(+) cells that was sufficient to drive repair. Of the myriad wound RORγt(+) populations, spatial transcriptomics and functional studies revealed that innate-like γδ T cells directed tissue repair by localizing to the wound front and boosting epithelial migration. These cells dominantly produced IL-17A/F in the wound microenvironment, which signaled directly to epithelia through IL-17RC to induce a migratory program. Comparative spatial transcriptomics of RORγt(+) cell-deficient and wild-type (WT) wound edges revealed differences in HIF1α signaling. WT migrating epithelia had robust nuclear HIF1α activation that was notably missing from RORγt(+) cell– and epithelial IL-17RC–deficient (Il17rc(EKO)) animals. Accordingly, epithelial-specific loss of HIF1α (Hif1a(EKO)) phenocopied the wound-healing defect of GFP-KI and Il17rc(EKO) mice. However, in contrast to GFP-KI wounds, recombinant IL-17A was unable to augment repair in Hif1a(EKO) mice, underscoring the necessity of this transcriptional effector mediating re-epithelialization downstream of IL-17A signaling. RORγt(+) cell–deficient and control animals had comparable levels of wound hypoxia, indicating that the failure of RORγt(+) cell–deficient animals to induce HIF1α was independent of oxygen sensing. Instead, IL-17A was sufficient to activate epithelial HIF1α both in vivo and in epithelial organoids. IL-17RC signaling rapidly induced activation of both ERK and AKT, which augmented HIF1α protein and transcript levels, but not stability, through mammalian target of rapamycin (mTOR). Acute hypoxia potently activated epithelial HIF1α in vitro, and this response was further boosted by IL-17A. By contrast, we uncovered a striking loss of mTOR and HIF1α in chronic hypoxia. Exogenous IL-17A rescued mTOR, and consequently HIF1α, under conditions of chronic hypoxia, indicating that IL-17A acts as a second signal to enable cell adaptation to low-oxygen environments. IL-17A induced a transcriptional and functional program of glycolytic metabolism in epithelia, which was dependent upon mTOR and HIF1α. The IL-17A-HIF1α-dependent program of glycolysis fueled epithelial migration, and pharmacological inhibition of glycolysis impaired wound re-epithelialization. CONCLUSION: Our findings upend a long-held view that hypoxia is sufficient to cell-autonomously induce HIF1α-mediated metabolic remodeling. We illustrate that IL-17A supplied by RORγt(+) γδ T cells is necessary for optimal HIF1α activation in the wound-edge epithelium. The IL-17A-HIF1α axis directed the metabolic rewiring of damaged epithelium toward a program of glycolysis to fuel migration. HIF1α and glycolysis are drivers of tumor progression and metastasis, raising the possibility that IL-17A or other immune-derived signals could drive these pathways in cancer. IL-17A is also central to the pathology of many autoimmune conditions, including psoriasis and inflammatory bowel disease. Thus, the IL-17A–HIF1α axis unveiled by our study may provide therapeutic opportunities for a range of epithelial inflammatory and metastatic diseases.

Gammaherpesviruses, such as human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), are species-specific, ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses have a natural tropism for B cells and usurp B cell differentiation to drive a unique and robust polyclonal germinal center response to establish a long-term latent reservoir in memory B cells. The robust polyclonal germinal center response driven by gammaherpesvirus infection increases the risk for B cell transformation. Unsurprisingly, many gammaherpesvirus cancers are derived from germinal center or post-germinal center B cells. The viral and host factors that influence the gammaherpesvirus-driven germinal center response are not clearly defined. We previously showed that host interleukin 17 receptor A (IL-17RA) signaling promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we found that T cell-intrinsic IL-17RA signaling recapitulates some proviral aspects of global IL-17RA signaling during MHV68 infection. Specifically, we found that T cell-intrinsic IL-17RA signaling supports the MHV68-driven germinal center response, the establishment of latency in the spleen, and viral reactivation in the spleen and peritoneal cavity. Our study unveils an unexpected finding where the T cell-specific IL-17RA signaling supports the establishment of a latent reservoir of a B cell-tropic gammaherpesvirus. IMPORTANCE Gammaherpesviruses, such as human EBV, establish lifelong infection in >95% of adults and are associated with B cell lymphomas. Gammaherpesviruses usurp the germinal center response to establish latent infection, and the germinal center B cells are thought to be the target of viral transformation. We previously found that global expression of IL-17RA promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we showed that T cell-intrinsic IL-17RA signaling is necessary to promote the MHV68-driven germinal center response by supporting CD4(+) T follicular helper cell expansion. We also found that T cell-intrinsic IL-17RA signaling contributes to but is not solely responsible for the systemic proviral role of IL-17RA signaling, highlighting the multifaceted function of IL-17RA signaling during MHV68 infection.

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases

Cancer stem cells (CSCs) are characterized by robust self-renewal and tumorigenesis and are responsible for metastasis, drug resistance, and angiogenesis. However, the molecular mechanisms for the regulation of CSC homeostasis are incompletely understood. This study demonstrated that the interleukin-17 (IL-17)B/IL-17RB signaling cascade promotes the self-renewal and tumorigenesis of CSCs by inducing Beclin-1 ubiquitination. We found that IL-17RB expression was significantly upregulated in spheroid cells and Lgr5-positive cells from the same tumor tissues of patients with gastric cancer (GC), which was closely correlated with the degree of cancer cell differentiation. Recombinant IL-17B (rIL-17B) promoted the sphere-formation ability of CSCs in vitro and enhanced tumor growth and metastasis in vivo. Interestingly, IL-17B induced autophagosome formation and cleavage-mediated transformation of LC3 in CSCs and 293T cells. Furthermore, inhibition of autophagy activation by ATG7 knockdown reversed rIL-17B-induced self-renewal of GC cells. In addition, we showed that IL-17B also promoted K63-mediated ubiquitination of Beclin-1 by mediating the binding of tumor necrosis factor receptor-associated factor 6 to Beclin-1. Silencing IL-17RB expression abrogated the effects of IL-17B on Beclin-1 ubiquitination and autophagy activation in GC cells. Finally, we showed that IL-17B level in the serum of GC patients was positively correlated with IL-17RB expression in GC tissues, and IL-17B could induce IL-17RB expression in GC cells. Overall, the results elucidate the novel functions of IL-17B for CSCs and suggest that the intervention of the IL-17B/IL-17RB signaling pathway may provide new therapeutic targets for the treatment of cancer.

ObjectiveBoth the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.DesignTo evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF ResultsWe identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL, MYRF, SEC16A and WDR78. For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate CYP2D6, GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15.ConclusionThis study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.

Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α (TNF-α) /interleukin (IL) -23/IL-17 axis, epidermal hyperproliferation, and dysregulated differentiation. Psoriasis is occasionally associated with autoimmune liver diseases such as autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), caused by autoimmunity against hepatocyte- or cholangiocyte-specific autoantigens, respectively. Overlap syndrome is a condition in which patients have features of both AIH and PBC. It has been reported that AIH, PBC, or the overlap syndrome can be triggered by certain drug therapies. A 65-year-old Japanese man developed increased serum levels of aspartate and alanine aminotransferases, and positive anti-nuclear and anti-mitochondrial M2 antibodies, along with neutropenia, at 4 weeks of treatment with an anti-IL-17 receptor A antibody brodalumab for generalized pustular psoriasis. Histological evaluation of the liver revealed interface hepatitis and non-suppurative destructive cholangitis, which is compatible with the overlap syndrome of AIH and PBC. This is the first case of AIH/PBC overlap syndrome during treatment with brodalumab for generalized pustular psoriasis. The relationship between brodalumab and AIH/PBC overlap syndrome should be further elucidated. The risk of autoimmune liver diseases in patients with psoriasis treated with brodalumab should be carefully considered.

Background Interleukin-17A (IL-17A) and IL-17F are involved in the pathogenesis of asthma and allergy. Interleukin-17 receptor A (IL-17RA), encoded by the IL17RA gene, is a common receptor for IL-17A and IL-17F. The aim of the present study was to evaluate the association of IL17RA gene variations with asthma, allergy, and lung function at school age in children prospectively followed up after hospitalization for bronchiolitis in early infancy. Methods Data on IL17RA rs4819553, rs4819554, and rs4819558 polymorphisms and clinical outcomes, including asthma and allergic rhinitis, were available for 145 former bronchiolitis patients at 5-7 years and for 125 at 11-13 years of age. One hundred children underwent impulse oscillometry at 5-7 years and 84 underwent flow-volume spirometry at 11-13 years of age. The IL17RA rs4819553, rs4819554 and rs4819558 were completely co-segregating in Finnish children in our previous studies. Results The distributions of the studied IL17RA wild versus variant genotypes and major versus minor allele frequencies did not differ between bronchiolitis cases and population controls. These variations showed no significant association with asthma or allergic rhinitis nor with lung function reduction at 5-7 or 11-13 years of ages. Only 5.6% to 6.4% of the variations were homozygous. Conclusions The IL17RA gene variations that were studied showed no association with susceptibility to severe bronchiolitis in infancy, nor with post-bronchiolitis asthma or lung function at school age. Future studies should evaluate other IL17RA polymorphisms and include more cases, and especially cases with homozygous variations.

Interleukin (IL)-17 is associated with autoimmunity. This study aimed to affirm the role of IL-17A, IL-17F and single nucleotide polymorphisms (SNPs) in genes related to them and their receptors in autoimmune type 1 diabetes (T1D) for Chinese population.In this study, 130 patients with autoimmune T1D and 140 non-T1D controls were included for analysis. Clinical and biochemical data were collected, and serum levels of IL-17A, IL-17F, IL-6, and high-sensitivity C reactive protein were measured using ELISA. The SNPs rs2275913, rs8193036, rs3819025, rs763780, rs879577, rs4819554, and rs708567 were genotyped using the SNaPshot assay.IL-17A levels were higher in patients with autoimmune T1D than in controls (median [IQR] 28.83[37.38] vs. 16.68[8.10], p 0.001) and high IL-17A was a risk factor for autoimmune T1D (odds ratio (OR), 1.013; 95% CI, 1.003-1.023; p = 0.013) after adjusting for confounding factors. Linear regression analysis revealed that logIncreased serum IL-17A, but not IL-17F, is a risk factor for autoimmune T1D. The GG genotype of IL17RA rs4819554 might decrease the risk for autoimmune T1D.

Despite the emergence of multiple biologic drug options for psoriasis, unmet treatment needs remain. Biologic therapies can vary in their effectiveness and adverse events, and many patients experience a loss of treatment effect over time. After lack of response, treatment may be switched to a biologic with a different mechanism of action. Brodalumab, a human interleukin-17 (IL-17) receptor A antagonist, is approved for the treatment of adult patients with moderate-to-severe psoriasis with inadequate response or loss of response to prior systemic therapies. Because brodalumab targets the IL-17 receptor instead of the ligand itself, it not only targets a broader set of IL-17 isoforms but also may be effective in patients who received prior IL-17 inhibitors or failed to respond to antindash;IL-17 treatment. This is supported by long-term evidence from clinical trials and real-world studies of patients receiving brodalumab who were previously treated with IL-17 inhibitors. Additionally, brodalumab produces reliable treatment effects after use of biologics with other mechanisms of action, such as tumor necrosis factoralpha; and IL-12/IL-23 inhibitors, as well as after the use of multiple biologic therapies. For patients with psoriasis with inadequate response to one or more biologic therapies, brodalumab is an option that has the ability to lead to long-term skin clearance. J Drugs Dermatol. 2022;21(3):364-370. doi:10.36849/JDD.6743.

Hypoxic microenvironment and circular RNAs (circRNAs) have shown critical implications in breast cancer (BC) progression. However, the specific functions and underlying mechanisms of circRNAs in BC under hypoxia remain largely unknown. We first screened for differentially expressed circRNAs in normoxic and hypoxic MCF-7 cells using circRNA microarray. A novel hypoxia-induced circRNA, circPFKFB4, was identified. Clinical investigation showed that circPFKFB4 was highly expressed in BC tissues and cell lines, and its overexpression was positively correlated with the advanced clinical stage and poor prognosis of BC patients. Functionally, circPFKFB4 promoted the proliferation of BC cells both

IL-17 contributes to the pathogenesis of certain autoimmune diseases, but conversely is essential for host defense against fungi. Antibody-based biologic drugs that neutralize IL-17 are effective in autoimmunity but can be accompanied by adverse side effects. Candida albicans is a commensal fungus that is the primary causative agent of oropharyngeal and disseminated candidiasis. Defects in IL-17 signaling cause susceptibility to candidiasis in mice and humans. A key facet of IL-17 receptor signaling involves RNA binding proteins (RBP), which orchestrate the fate of target mRNA transcripts. In tissue culture models we showed that the RBP AT-rich interacting protein 5a (Arid5a) promotes the stability and/or translation of multiple IL-17-dependent mRNAs. Moreover, during OPC, Arid5a is elevated within the oral mucosa in an IL-17-dependent manner. However, the contribution of Arid5a to IL-17-driven events in vivo is poorly defined. Here, we used CRISPR/Cas9 to generate mice lacking Arid5a. Arid5a-/- mice were fully resistant to experimental autoimmune encephalomyelitis (EAE), an autoimmune setting in which IL-17 signaling drives pathology. Surprisingly, Arid5a-/- mice were resistant to OPC and systemic candidiasis, similar to immunocompetent WT mice and contrasting with mice defective in IL-17 signaling. Therefore, Arid5a-dependent signals mediate pathology in autoimmunity yet are not required for immunity to candidiasis, indicating that selective targeting of IL-17 signaling pathway components may be a viable strategy for development of therapeutics that spare IL-17-driven host defense.