RESUMO
INTRODUCTION: The treatment of multiple myeloma (MM) is evolving rapidly. Quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies have emerged as standard-of-care options for newly diagnosed MM, and numerous novel therapies have been approved for relapsed/refractory MM. However, there remains a need for novel options in multiple settings, including refractoriness to frontline standards of care. AREAS COVERED: Targeting degradation of IKZF1 and IKZF3 - Ikaros and Aiolos - through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023), this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. EXPERT OPINION: Emerging data suggest that iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings and, pending phase 3 findings, may provide additional treatment options for patients with MM.
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Fator de Transcrição Ikaros , Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Fator de Transcrição Ikaros/metabolismo , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Talidomida/farmacologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proteólise/efeitos dos fármacos , Terapia de Alvo Molecular , Agentes de Imunomodulação/uso terapêutico , Agentes de Imunomodulação/farmacologia , Ensaios Clínicos como Assunto , Animais , Piperidonas , Morfolinas , Receptores de Interleucina-17 , Proteínas Adaptadoras de Transdução de Sinal , FtalimidasRESUMO
BACKGROUND: We previously identified Il17RB, a member of the IL17 superfamily, as a candidate marker gene for endometrial aging. While IL17RB has been linked to inflammation and malignancies in several organ systems, its function in the endometrium has not been investigated and is thus poorly understood. In the present study, we performed a functional analysis of this receptor with the aim of determining the effects of its age-associated overexpression on the uterine environment. METHODS: We analyzed IL17RB-related signaling pathways and downstream gene expression in an immortalized human endometrial glandular epithelial cell line ("hEM") forced to express the receptor via lentiviral transduction ("IL17RB-hEM"). We also prepared endometrial organoids from human endometrial tissue sourced from hysterectomy patients ("patient-derived EOs") and exposed them to cytokines that are upregulated by IL17RB expression to investigate changes in organoid-forming capacity and senescence markers. We analyzed RNA-seq data (GEO accession number GSE132886) from our previous study to identify the signaling pathways associated with altered IL17RB expression. We also analyzed the effects of the JNK pathway on organoid-forming capacity. RESULTS: Stimulation with interleukin 17B enhanced the NF-κB pathway in IL17RB-hEM, resulting in significantly elevated expression of the genes encoding the senescence associated secretory phenotype (SASP) factors IL6, IL8, and IL1ß. Of these cytokines, IL1ß inhibited endometrial organoid growth. Bioinformatics analysis showed that the JNK signaling pathway was associated with age-related variation in IL17RB expression. When IL17RB-positive cells were cultured in the presence of IL17B, their organoid-forming capacity was slightly but non-significantly lower than in unexposed IL17RB-positive cells, but when IL17B was paired with a JNK inhibitor (SP600125), it was restored to control levels. Further, IL1ß exposure significantly reduced organoid-forming capacity and increased p21 expression in endometrial organoids relative to non-exposure (control), but when IL1ß was paired with SP600125, both indicators were restored to levels comparable to the control condition. CONCLUSIONS: We have revealed an association between IL17RB, whose expression increases in the endometrial glandular epithelium with advancing age, and cellular senescence. Using human endometrial organoids as in vitro model, we found that IL1ß inhibits cell proliferation and leads to endometrial senescence via the JNK pathway.
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Senescência Celular , Endométrio , Receptores de Interleucina-17 , Transdução de Sinais , Humanos , Feminino , Endométrio/metabolismo , Endométrio/citologia , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/genética , Senescência Celular/genética , Organoides/metabolismo , Linhagem CelularRESUMO
Background: Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses. Methods: We generated a conditional knockout of Il17ra in Tregs by crossing Foxp3-YFP-Cre mice to Il17ra-flox mice (Il17ra ΔTreg mice). Subsequently, we adoptively transferred bone marrow cells from Il17ra ΔTreg mice to a mouse model of sporadic colorectal cancer (Cdx2-Cre +/Apc F/+), to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors, and compared to those of human tumor infiltrating Treg cells. Results: IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function. Conclusion: IL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC.
Assuntos
Interleucina-17 , Camundongos Knockout , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Interleucina-17/metabolismo , Camundongos , Humanos , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Modelos Animais de DoençasRESUMO
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.
Assuntos
Artrite Reumatoide , Antígeno B7-H1 , Interleucina-17 , Macrófagos , Receptores de Interleucina-17 , Fator de Transcrição STAT3 , Transdução de Sinais , Interleucina-17/metabolismo , Animais , Fator de Transcrição STAT3/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/tratamento farmacológico , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Camundongos , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/genética , Antocianinas/farmacologia , Artrite Experimental/imunologia , Humanos , Modelos Animais de Doenças , Fagocitose/efeitos dos fármacos , Masculino , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , EferocitoseRESUMO
Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.
Assuntos
Proteínas de Ciclo Celular , Oxindóis , Proteólise , Ubiquitina-Proteína Ligases , Humanos , Animais , Proteólise/efeitos dos fármacos , Camundongos , Ubiquitina-Proteína Ligases/metabolismo , Oxindóis/farmacologia , Oxindóis/metabolismo , Oxindóis/química , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Células HEK293 , Relação Estrutura-Atividade , Complexo de Endopeptidases do Proteassoma/metabolismo , Azepinas/farmacologia , Azepinas/química , Azepinas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Feminino , Proteínas que Contêm Bromodomínio , Receptores de Interleucina-17RESUMO
Helicobacter pylori is a Gram-negative pathogen that colonizes the stomach, induces inflammation, and drives pathological changes in the stomach tissue, including gastric cancer. As the principal cytokine produced by Th17 cells, IL-17 mediates protective immunity against pathogens by inducing the activation and mobilization of neutrophils. Whereas IL-17A is largely produced by lymphocytes, the IL-17 receptor is expressed in epithelial cells, fibroblasts, and hematopoietic cells. Loss of the IL-17RA in mice results in impaired antimicrobial responses to extracellular bacteria. In the context of H. pylori infection, this is compounded by extensive inflammation in Il17ra-/- mice. In this study, Foxa3creIl17rafl/fl (Il17raΔGI-Epi) and Il17rafl/fl (control) mice were used to test the hypothesis that IL-17RA signaling, specifically in epithelial cells, protects against severe inflammation after H. pylori infection. The data indicate that Il17raΔGI-Epi mice develop increased inflammation compared with controls. Despite reduced Pigr expression, levels of IgA increased in the gastric wash, suggesting significant increase in Ag-specific activation of the T follicular helper/B cell axis. Gene expression analysis of stomach tissues indicate that both acute and chronic responses are significantly increased in Il17raΔGI-Epi mice compared with controls. These data suggest that a deficiency of IL-17RA in epithelial cells is sufficient to drive chronic inflammation and hyperactivation of the Th17/T follicular helper/B cell axis but is not required for recruitment of polymorphonuclear neutrophils. Furthermore, the data suggest that fibroblasts can produce chemokines in response to IL-17 and may contribute to H. pylori-induced inflammation through this pathway.
Assuntos
Infecções por Helicobacter , Receptores de Interleucina-17 , Animais , Camundongos , Células Epiteliais/metabolismo , Infecções por Helicobacter/imunologia , Helicobacter pylori , Inflamação/metabolismo , Interleucina-17/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismoRESUMO
Fracture healing is a complex series of events that requires a local inflammatory reaction to initiate the reparative process. This inflammatory reaction is important for stimulating the migration and proliferation of mesenchymal progenitor cells from the periosteum and surrounding tissues to form the cartilaginous and bony calluses. The proinflammatory cytokine interleukin (IL)-17 family has gained attention for its potential regenerative effects; however, the requirement of IL-17 signaling within mesenchymal progenitor cells for normal secondary fracture healing remains unknown. The conditional knockout of IL-17 receptor a (Il17ra) in mesenchymal progenitor cells was achieved by crossing Il17raF/F mice with Prx1-cre mice to generate Prx1-cre; Il17raF/F mice. At 3 months of age, mice underwent experimental unilateral mid-diaphyseal femoral fractures and healing was assessed by micro-computed tomography (µCT) and histomorphometric analyses. The effects of IL-17RA signaling on the osteogenic differentiation of fracture-activated periosteal cells was investigated in vitro. Examination of the intact skeleton revealed that the conditional knockout of Il17ra decreased the femoral cortical porosity but did not affect any femoral trabecular microarchitectural indices. After unilateral femoral fractures, Il17ra conditional knockout impacted the cartilage and bone composition of the fracture callus that was most evident early in the healing process (day 7 and 14 post-fracture). Furthermore, the in vitro treatment of fracture-activated periosteal cells with IL-17A inhibited osteogenesis. This study suggests that IL-17RA signaling within Prx1+ mesenchymal progenitor cells can influence the early stages of endochondral ossification during fracture healing.
Assuntos
Fraturas do Fêmur , Proteínas de Homeodomínio , Células-Tronco Mesenquimais , Receptores de Interleucina-17 , Animais , Camundongos , Consolidação da Fratura , Inflamação , Osteogênese , Microtomografia por Raio-X , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Proteínas de Homeodomínio/metabolismoRESUMO
BACKGROUND: The human interleukin-17 (IL-17) family comprises IL-17A to IL-17 F; their receptors are IL-17RA to IL-17RE. Evidence revealed that these cytokines can have a tumor-supportive or anti-tumor impact on human malignancies. The purpose of this study was to assess the expression of CXCR2, IL-17RA, and IL-17RC genes at the mRNA level as well as tissue and serum levels of IL-17A, vascular endothelial growth factor (VEGF), and transforming growth factor ß (TGF-ß) in patients with bladder cancer (BC) compared to control. RESULTS: This study showed that gene expression of IL-17RA, IL-17RC, and CXCR2 in the tumoral tissue of BC patients was significantly upregulated compared with normal tissue. The findings disclosed a significant difference in the serum and tissue concentrations of IL-17A, VEGF, and TGF-ß between the patient and the control groups, as well as tumor and normal tissues. CONCLUSION: This study reveals notable dysregulation of CXCR2, IL-17RA, and IL-17RC genes, alongside changes in IL-17A, VEGF, and TGF-ß levels in patients with BC than in controls. These findings indicate their possible involvement in BC development and their potential as diagnostic and therapeutic targets.
Assuntos
Interleucina-17 , Neoplasias da Bexiga Urinária , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Angiogênese , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Quimiocinas , Neoplasias da Bexiga Urinária/genética , Fator de Crescimento Transformador betaRESUMO
Macrophage recruitment to the injured nerve initiates a cascade of events, including myelin debris clearance and nerve trophic factor secretion, which contribute to proper nerve tissue repair. However, the mechanism of macrophage recruitment is still unclear. Here, by comparing wild-type with Mlkl-/- and Sarm1-/- mice, two mouse strains with impaired myelin debris clearance after peripheral nerve injury, we identify interleukin-17B (IL-17B) as a key regulator of macrophage recruitment. Schwann-cell-secreted IL-17B acts in an autocrine manner and binds to IL-17 receptor B to promote macrophage recruitment, and global or Schwann-cell-specific IL-17B deletion reduces macrophage infiltration, myelin clearance, and axon regeneration. We also show that the IL-17B signaling pathway is defective in the injured central nerves. These results reveal an important role for Schwann cell autocrine signaling during Wallerian degeneration and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.
Assuntos
Axônios , Interleucina-17 , Animais , Camundongos , Receptores de Interleucina-17 , Regeneração Nervosa , Células de Schwann , MacrófagosRESUMO
BACKGROUND: Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood-brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction-induced HF. METHODS AND RESULTS: Male Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno-associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate-dextran 10 kDa+rhodamine-dextran 70 kDa). Compared with sham-operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate-dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin-1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin-1 and tight junction-associated proteins in the PVN. CONCLUSIONS: Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.
Assuntos
Barreira Hematoencefálica , Fluoresceína-5-Isotiocianato , Interleucina-17 , Infarto do Miocárdio , Núcleo Hipotalâmico Paraventricular , Transdução de Sinais , Animais , Masculino , Ratos , Barreira Hematoencefálica/metabolismo , Caveolina 1/metabolismo , Citocinas/metabolismo , Dextranos/metabolismo , Dextranos/farmacologia , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceínas/metabolismo , Fluoresceínas/farmacologia , Insuficiência Cardíaca , Interleucina-17/metabolismo , Isotiocianatos/metabolismo , Isotiocianatos/farmacologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Ratos Sprague-Dawley , Receptores de Interleucina-17/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
Activation of Th17 cell responses, including the production of IL-17A and IL-21, contributes to host defense and inflammatory responses by coordinating adaptive and innate immune responses. IL-17A and IL-17F signal through a multimeric receptor, which includes the IL-17 receptor A (IL-17RA) subunit and the IL-17RC subunit. IL-17RA is expressed by many cell types, and data from previous studies suggest that loss of IL-17 receptor is required to limit immunopathology in the Helicobacter pylori model of infection. Here, an Il17ra-/- mouse was generated on the FVB/n background, and the role of IL-17 signaling in the maintenance of barrier responses to H. pylori was investigated. Generating the Il17ra-/- on the FVB/n background allowed for the examination of responses in the paragastric lymph node and will allow for future investigation into carcinogenesis. While uninfected Il17ra-/- mice do not develop spontaneous gastritis following H. pylori infection, Il17ra-/- mice develop severe gastric inflammation accompanied by lymphoid follicle production and exacerbated production of Th17 cytokines. Increased inflammation in the tissue, increased IgA levels in the lumen, and reduced production of Muc5ac in the corpus correlate with increased H. pylori-induced paragastric lymph node activation. These data suggest that the cross talk between immune cells and epithelial cells regulates mucin production, IgA production, and translocation, impacting the integrity of the gastric mucosa and therefore activating of the adaptive immune response.
Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , Camundongos , Animais , Interleucina-17/genética , Interleucina-17/metabolismo , Helicobacter pylori/fisiologia , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Mucosa Gástrica/metabolismo , Inflamação/metabolismo , Imunoglobulina A/metabolismoRESUMO
Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.
Assuntos
Interleucina-17 , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Receptores de Interleucina-17/genética , Camundongos Knockout , Transdução de Sinais , Neoplasias Pancreáticas/patologiaRESUMO
Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Camundongos , Animais , Receptores de Interleucina-17/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Osteossarcoma/patologia , Diferenciação Celular , Neoplasias Ósseas/patologiaRESUMO
IL-17 immune responses in cancer are controversial, with both tumor-promoting and tumor-repressing effects observed. To clarify the role of IL-17 signaling in cancer progression, we used syngeneic tumor models from different tissue origins. We found that deficiencies in host IL-17RA or IL-17A/F expression had varying effects on the in vivo growth of different solid tumors including melanoma, sarcoma, lymphoma, and leukemia. In each tumor type, the absence of IL-17 led to changes in the expression of mediators associated with inflammation and metastasis in the tumor microenvironment. Furthermore, IL-17 signaling deficiencies in the hosts resulted in decreased anti-tumor CD8+ T cell immunity and caused tumor-specific changes in several lymphoid cell populations. Our findings were associated with distinct patterns of IL-17A/F cytokine and receptor subunit expression in the injected tumor cell lines. These patterns affected tumor cell responsiveness to IL-17 and downstream intracellular signaling, leading to divergent effects on cancer progression. Additionally, we identified IL-17RC as a critical determinant of the IL-17-mediated response in tumor cells and a potential biomarker for IL-17 signaling effects in tumor progression. Our study offers insight into the molecular mechanisms underlying IL-17 activities in cancer and lays the groundwork for developing personalized immunotherapies.
Assuntos
Neoplasias , Receptores de Interleucina-17 , Humanos , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Interleucina-17 , Transdução de Sinais , Linfócitos T CD8-Positivos , Inflamação , Neoplasias/genéticaRESUMO
Psoriasis remains a highly prevalent condition in the United States and worldwide. Preclinical research has been triumphant in elucidating the critical immunological pathways involved in psoriasis. There has been an evolution in biologics that paralleled the understanding of these pathways beginning with anti-tumor necrosis factor (TNF) inhibitors and now most recently the interleukin (IL)-23 and IL-17 axes. Numerous evidence-based studies demonstrate the efficacy of these agents for skin clearance in moderate-to-severe plaque psoriasis. Brodalumab, a fully humanized IL-17 receptor A (IL-17RA) antagonist, is wholly unique in that it binds to a cytokine receptor and not a cytokine itself unlike the other biologics indicated for psoriasis. This unique mechanism has lent an advantage where not only is brodalumab effective in treating moderate-to-severe plaque psoriasis, but it is also successful in psoriasis patients whose disease did not respond to other biologics. This review provides a summary of the efficacy of brodalumab in plaque psoriasis and difficult-to-treat locations (ie, scalp, nail, palmoplantar), in patients with psoriasis who failed to achieve minimum clearance with other biologics, and it illuminates the most recent pharmacovigilance data obtained from the past 5 years. Furthermore, the cost effectiveness of brodalumab is also discussed. J Drugs Dermatol. 2023;22:10(Suppl 1):s5-14.
Assuntos
Produtos Biológicos , Psoríase , Humanos , Anticorpos Monoclonais/efeitos adversos , Receptores de Interleucina-17 , Análise Custo-Benefício , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Interleucina-23 , Resultado do TratamentoRESUMO
Introduction: Ets1 is a lymphoid-enriched transcription factor that regulates B- and Tcell functions in development and disease. Mice that lack Ets1 (Ets1 KO) develop spontaneous autoimmune disease with high levels of autoantibodies. Naïve CD4 + T cells isolated from Ets1 KO mice differentiate more readily to Th17 cells that secrete IL-17, a cytokine implicated in autoimmune disease pathogenesis. To determine if increased IL-17 production contributes to the development of autoimmunity in Ets1 KO mice, we crossed Ets1 KO mice to mice lacking the IL-17 receptor A subunit (IL17RA KO) to generate double knockout (DKO) mice. Methods: In this study, the status of the immune system of DKO and control mice was assessed utilizing ELISA, ELISpot, immunofluorescent microscopy, and flow cytometric analysis of the spleen, lymph node, skin. The transcriptome of ventral neck skin was analyzed through RNA sequencing. S. aureus clearance kinetics in in exogenously infected mice was conducted using bioluminescent S. aureus and tracked using an IVIS imaging experimental scheme. Results: We found that the absence of IL17RA signaling did not prevent or ameliorate the autoimmune phenotype of Ets1 KO mice but rather that DKO animals exhibited worse symptoms with striking increases in activated B cells and secreted autoantibodies. This was correlated with a prominent increase in the numbers of T follicular helper (Tfh) cells. In addition to the autoimmune phenotype, DKO mice also showed signs of immunodeficiency and developed spontaneous skin lesions colonized by Staphylococcus xylosus. When DKO mice were experimentally infected with Staphylococcus aureus, they were unable to clear the bacteria, suggesting a general immunodeficiency to staphylococcal species. γδ T cells are important for the control of skin staphylococcal infections. We found that mice lacking Ets1 have a complete deficiency of the γδ T-cell subset dendritic epidermal T cells (DETCs), which are involved in skin woundhealing responses, but normal numbers of other skin γδ T cells. To determine if loss of DETC combined with impaired IL-17 signaling might promote susceptibility to staph infection, we depleted DETC from IL17RA KO mice and found that the combined loss of DETC and impaired IL-17 signaling leads to an impaired clearance of the infection. Conclusions: Our studies suggest that loss of IL-17 signaling can result in enhanced autoimmunity in Ets1 deficient autoimmune-prone mice. In addition, defects in wound healing, such as that caused by loss of DETC, can cooperate with impaired IL-17 responses to lead to increased susceptibility to skin staph infections.
Assuntos
Doenças Autoimunes , Proteína Proto-Oncogênica c-ets-1 , Receptores de Interleucina-17 , Infecções Estafilocócicas , Animais , Camundongos , Autoanticorpos , Doenças Autoimunes/genética , Autoimunidade , Interleucina-17 , Receptores de Interleucina-17/metabolismo , Staphylococcus aureus , Proteína Proto-Oncogênica c-ets-1/metabolismoRESUMO
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease. Mature IL-17A is a homodimer that binds to the extracellular type-III fibronectin D1:D2-dual domain of its cognate IL-17 receptor A (IL-17RA). In this study, we systematically examined the structural basis, thermodynamics property, and dynamics behavior of IL-17RA/IL-17A interaction and computationally identified two continuous hotspot regions separately from different monomers of IL-17A homodimer that contribute significantly to the interaction, namely I-shaped and U-shaped segments, thus rendered as a peptide-mediated protein-protein interaction (PmPPI). Self-inhibitory peptides (SIPs) are derived from the two segments to disrupt IL-17RA/IL-17A interaction by competitively rebinding to the IL-17A-binding pocket on IL-17RA surface, which, however, only have a weak affinity and low specificity for IL-17RA due to lack of the context support of intact IL-17A protein, thus exhibiting a large flexibility and intrinsic disorder when splitting from the protein context and incurring a considerable entropy penalty when rebinding to IL-17RA. The U-shaped segment is further extended, mutated and stapled by a disulfide bridge across its two strands to obtain a number of double-stranded cyclic SIPs, which are partially ordered and conformationally similar to their native status at IL-17RA/IL-17A complex interface. Experimental fluorescence polarization assays substantiate that the stapling can moderately or considerably improve the binding affinity of U-shaped segment-derived peptides by 2-5-fold. In addition, computational structural modeling also reveals that the stapled peptides can bind in a similar mode with the native crystal conformation of U-shaped segment in IL-17RA pocket, where the disulfide bridge is out of the pocket for avoiding intervene of the peptide binding.
Assuntos
Interleucina-17 , Receptores de Interleucina-17 , Interleucina-17/química , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Receptores de Interleucina-17/química , Receptores de Interleucina-17/metabolismo , Peptídeos/química , Modelos Moleculares , Ligação ProteicaRESUMO
Autoimmune uveitis is an inflammatory disorder of the eye triggered by the responses of autoreactive T cells to ocular autoantigens. This study aims to understand the role of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-producing T helper (ThGM) cells in the pathophysiology of mouse experimental autoimmune uveitis (EAU). We established an EAU model by immunizing mice with interphotoreceptor retinoid-binding protein (IRBP) 651-670. Splenic or eye-infiltrating ThGM cells were analyzed and enriched by flow cytometry according to the levels of an array of surface markers, transcription factors, and cytokines. Lentiviral transduction was conducted to silence or overexpress the target gene in differentiated ThGM cells. The adoptive transfer was applied to determine the pathogenicity of ThGM cells in vivo. We found that ThGM cells were present in the spleen and the eye after EAU induction. Both splenic and eye-infiltrating ThGM cells were phenotypically CD4+CCR7-CXCR3-CCR6-CCR10hi. Eye-infiltrating ThGM cells up-regulated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and IL-17 receptor C (IL-17RC) relative to splenic ThGM cells. IL-17RC overexpression enabled interleukin-17A (IL-17A)-induced up-regulation of IL-1ß and IL-6 production in ThGM cells. Adoptive transfer of IL-17RC overexpressing ThGM cells exacerbated EAU severity, as evidenced by a higher histology score as well as increased pro-inflammatory cytokines and inflammatory cells in the eye. However, IL-17RC-silenced ThGM cells did not impact EAU. Therefore, for the first time, this study unveils the essential pro-inflammatory role of IL-17RC-expressing ThGM cells in EAU pathophysiology. We discovered a novel mechanism underlying the pathophysiology of autoimmune uveitis.
Assuntos
Doenças Autoimunes , Uveíte , Animais , Camundongos , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas do Olho/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Granulócitos , Interleucina-6 , Macrófagos/metabolismo , Receptores de Interleucina-17 , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th17/metabolismo , VirulênciaRESUMO
SARS-CoV-2 has caused an estimated 7 million deaths worldwide to date. A secreted SARS-CoV-2 accessory protein, known as open reading frame 8 (ORF8), elicits inflammatory pulmonary cytokine responses and is associated with disease severity in COVID-19 patients. Recent reports proposed that ORF8 mediates downstream signals in macrophages and monocytes through the IL-17 receptor complex (IL-17RA, IL-17RC). However, generally IL-17 signals are found to be restricted to the nonhematopoietic compartment, thought to be due to rate-limiting expression of IL-17RC. Accordingly, we revisited the capacity of IL-17 and ORF8 to induce cytokine gene expression in mouse and human macrophages and monocytes. In SARS-CoV-2-infected human and mouse lungs, IL17RC mRNA was undetectable in monocyte/macrophage populations. In cultured mouse and human monocytes and macrophages, ORF8 but not IL-17 led to elevated expression of target cytokines. ORF8-induced signaling was fully preserved in the presence of anti-IL-17RA/RC neutralizing Abs and in Il17ra-/- cells. ORF8 signaling was also operative in Il1r1-/- bone marrow-derived macrophages. However, the TLR/IL-1R family adaptor MyD88, which is dispensable for IL-17R signaling, was required for ORF8 activity yet MyD88 is not required for IL-17 signaling. Thus, we conclude that ORF8 transduces inflammatory signaling in monocytes and macrophages via MyD88 independently of the IL-17R.
Assuntos
COVID-19 , Fases de Leitura Aberta , SARS-CoV-2 , Animais , Humanos , Camundongos , COVID-19/imunologia , COVID-19/virologia , Citocinas/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , SARS-CoV-2/metabolismoRESUMO
Head and neck squamous cell carcinoma (HNSCC) is a common tumour type in otorhinolaryngology, and its occurrence is related to long-term exposure to tobacco and alcohol. Recently, HPV infection has become an increasingly important contributor to HNSCC, and HPV-associated HNSCC has a different clinical course and better prognosis than non-HPV-associated HNSCC. However, the exact molecular mechanism of HNSCC is unclear. Here, we obtained data from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) to analyse the mitophagy process and related influencing factors of HPV-associated HNSCC via the integration of bioinformatics analysis and experimental validation. We found that in HPV-associated HNSCC, process of mitophagy affects tumour development, immune cell infiltration and prognosis. In the mitophagy process of HPV-related HNSCC: NOS2, IL17REL, TMSB15A, TUBB4A and other hub genes showed significantly higher expression levels than in non-HPV-related HNSCC. Furthermore, this was also confirmed by quantitative real-time PCR (qRTâPCR), which was used to detect the expression of differentially expressed genes in HNSCC tissues. Furthermore, we found that the unique immunological characteristics by expressing CD8+ T cell in a high level in HPV-related HNSCC, and the scores obtained from the score model affected the prognosis of patients. In conclusion, our study revealed the unique biomolecular signature of mitophagy in HPV-associated HNSCC, which may contribute to the development of precise treatment regimens for HPV-associated HNSCC patients.