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Investigative Ophthalmology & Visual... Sep 2023This study aimed to elucidate the impact of upadacitinib, a Janus kinase 1 (JAK1)-specific inhibitor, on experimental autoimmune uveitis (EAU) and explore its underlying...
PURPOSE
This study aimed to elucidate the impact of upadacitinib, a Janus kinase 1 (JAK1)-specific inhibitor, on experimental autoimmune uveitis (EAU) and explore its underlying mechanisms.
METHODS
We utilized single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to investigate the JAK/signal transducer and activator of transcription (STAT) pathway in peripheral blood mononuclear cells (PBMCs) of 12 patients with Vogt-Koyanagi-Harada (VKH) disease and cervical draining lymph node (CDLN) cells of EAU. After treating EAU with upadacitinib, we analyzed immune cell gene expression and cell-cell communication by integrating scRNA data. Additionally, we applied flow cytometry and western blot to analyze the CDLN cells.
RESULTS
The JAK/STAT pathway was found to be upregulated in patients with VKH disease and EAU. Upadacitinib effectively alleviated EAU symptoms, reduced JAK1 protein expression, and suppressed pathogenic CD4 T cell (CD4TC) proliferation and pathogenicity while promoting Treg proliferation. The inhibition of pathogenic CD4TCs by upadacitinib was observed in both flow cytometry and scRNA data. Additionally, upadacitinib was found to rescue the interferon-stimulated gene 15 (ISG15)+ CD4TCs and CD8 T and B cell ratios and reduce expression of inflammatory-related genes. Upadacitinib demonstrated the ability to inhibit abnormally activated cell-cell communication, particularly the CXCR4-mediated migration pathway, which has been implicated in EAU pathogenesis. CXCR4 inhibitors showed promising therapeutic effects in EAU.
CONCLUSIONS
Our findings indicate that the JAK1-mediated signaling pathway is significantly upregulated in uveitis, and upadacitinib exhibits therapeutic efficacy against EAU. Furthermore, targeting the CXCR4-mediated migration pathway could be a promising therapeutic strategy.
Topics: Humans; Signal Transduction; Janus Kinases; Leukocytes, Mononuclear; STAT Transcription Factors; Uveitis; Uveomeningoencephalitic Syndrome; Single-Cell Analysis
PubMed: 37713206
DOI: 10.1167/iovs.64.12.28 -
Journal of Cellular and Molecular... Apr 2022A subset of cytokines triggers the JAK-STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these... (Review)
Review
A subset of cytokines triggers the JAK-STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these cytokines are dimers/trimers of transmembrane proteins devoid of intracellular kinase activity. Instead, they rely on Janus kinases (JAKs) for signal transduction. Classical JAK-STAT signalling involves phosphorylation of cytokine receptors' intracellular tyrosines, which subsequently serve as docking sites for the recruitment and activation of STATs. However, there is evidence to show that several cytokine receptors also use a noncanonical, receptor tyrosine-independent path to induce activation of STAT proteins. We identified two main alternative modes of STAT activation. The first involves an association between a tyrosine-free region of the cytokine receptor and STATs, while the second seems to depend on a direct interaction between JAK and STAT proteins. We were able to identify the use of noncanonical mechanisms by almost a dozen cytokine receptors, suggesting they have some importance. These alternative pathways and the receptors that employ them are discussed in this review.
Topics: Janus Kinases; Phosphorylation; Receptors, Cytokine; STAT Transcription Factors; Signal Transduction
PubMed: 35238133
DOI: 10.1111/jcmm.17168 -
EBioMedicine Nov 2023JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders.... (Review)
Review
JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.
Topics: Humans; Janus Kinase Inhibitors; TYK2 Kinase; Autoimmune Diseases; Cytokines; Psoriasis; Janus Kinase 1
PubMed: 37863021
DOI: 10.1016/j.ebiom.2023.104840 -
American Journal of Physiology. Cell... Oct 2022Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of target-directed, small molecule inhibitors used to treat hematologic malignancies, inflammatory... (Review)
Review
Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of target-directed, small molecule inhibitors used to treat hematologic malignancies, inflammatory diseases, and autoimmune disorders. Recently, TKIs have also gained interest as potential antiplatelet-directed therapeutics that could be leveraged to reduce pathologic thrombus formation and atherothrombotic complications, while minimally affecting platelet hemostatic function. This review provides a mechanistic overview and summarizes the known effects of tyrosine kinase inhibitors on platelet signaling and function, detailing prominent platelet signaling pathways downstream of the glycoprotein VI (GPVI) receptor, integrin αβ, and G protein-coupled receptors (GPCRs). This review focuses on mechanistic as well as clinically relevant and emerging TKIs targeting major families of tyrosine kinases including but not limited to Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (Syk), Src family kinases (SFKs), Janus kinases (JAK), and signal transducers and activators of transcription (STAT) and evaluates their effects on platelet aggregation and adhesion, granule secretion, receptor expression and activation, and protein phosphorylation events. In summation, this review highlights current advances and knowledge on the effects of select TKIs on platelet biology and furthers insight on signaling pathways that may represent novel druggable targets coupled to specific platelet functional responses.
Topics: Agammaglobulinaemia Tyrosine Kinase; Blood Platelets; Hemostatics; Janus Kinases; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Kinase Inhibitors; Syk Kinase; Tyrosine; src-Family Kinases
PubMed: 35938677
DOI: 10.1152/ajpcell.00040.2022 -
Frontiers in Immunology 2023Primary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T...
BACKGROUND
Primary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T cells. Towards this end, ruxolitinib treatment or IFNg neutralization (aIFNg) lessens immunopathology in a model of pHLH in which perforin-deficient mice (-/-) are infected with Lymphocytic Choriomeningitis virus (LCMV). However, neither agent completely eradicates inflammation. Two studies combining ruxolitinib with aIFNg report conflicting results with one demonstrating improvement and the other worsening of disease manifestations. As these studies used differing doses of drugs and varying LCMV strains, it remained unclear whether combination therapy is safe and effective.
METHODS
We previously showed that a ruxolitinib dose of 90 mg/kg lessens inflammation in -/- mice infected with LCMV-Armstrong. To determine whether this dose controls inflammation induced by a different LCMV strain, we administered ruxolitinib at 90mg/kg to -/- mice infected with LCMV-WE. To elucidate the impacts of single agent versus combination therapy, -/- animals were infected with LCMV, treated or not with ruxolitinib, aIFNg or both agents, and analyzed for disease features and the transcriptional impacts of therapy within purified CD8 T cells.
RESULTS
Ruxolitinib is well-tolerated and controls disease regardless of the viral strain used. aIFNg, administered alone or with ruxolitinib, is most effective at reversing anemia and reducing serum IFNg levels. In contrast, ruxolitinib appears better than aIFNg, and equally or more effective than combination therapy, at lessening immune cell expansion and cytokine production. Each treatment targets distinct gene expression pathways with aIFNg downregulating IFNg, IFNa, and IL-6-STAT3 pathways, and ruxolitinib downregulating IL-6-STAT3, glycolysis, and reactive oxygen species pathways. Unexpectedly, combination therapy is associated with upregulation of genes driving cell survival and proliferation.
CONCLUSIONS
Ruxolitinib is tolerated and curtails inflammation regardless of the inciting viral strain and whether it is given alone or in combination with aIFNg. When administered at the doses used in this study, the combination of ruxolitinb and aIFNg appears no better than treatment with either drug alone in lessening inflammation. Further studies are warranted to elucidate the optimal doses, schedules, and combinations of these agents for the treatment of patients with pHLH.
Topics: Animals; Mice; Janus Kinases; Interferon-gamma; Lymphohistiocytosis, Hemophagocytic; Interleukin-6; Lymphocytic choriomeningitis virus; Inflammation
PubMed: 37228616
DOI: 10.3389/fimmu.2023.1137037 -
Immunological Medicine Sep 2023Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in... (Review)
Review
Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in inflammatory diseases such as atopic dermatitis (AD). Large-scale clinical trials on AD utilizing JAK inhibitors and biologic reagents, such as dupilumab, which targets the IL-4Rα receptor subunit of the Th2 cytokines IL-4 and IL-13, have yielded highly favorable results in comparison to traditional therapies. This indicates that therapeutic strategies based on molecular biology are efficacious in clinical settings. However, in September 2021, the U.S. Food and Drug Administration (FDA) indicated that tofacitinib, a JAK inhibitor, may carry various risks, including severe heart disease. Similar concerns have been raised for other JAK inhibitors, and further safety evaluations are underway. Thus, human biology involving JAKs appeared more complicated than we expected. In this article, we provide an overview of the molecular mechanisms of AD and examine the molecular targeting drugs for AD from the perspective of JAK-related biology.
Topics: United States; Humans; Janus Kinases; Dermatitis, Atopic; Janus Kinase Inhibitors; Cytokines; Interleukin-13
PubMed: 37254967
DOI: 10.1080/25785826.2023.2214324 -
Frontiers in Immunology 2024Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with... (Review)
Review
Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Psoriasis; Biological Products; Janus Kinases
PubMed: 38444845
DOI: 10.3389/fimmu.2024.1341632 -
Journal of the American Academy of... Jan 2022Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a... (Review)
Review
Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.
Topics: Humans; Interleukin-12; Janus Kinase 1; Janus Kinase Inhibitors; Janus Kinases; Psoriasis; TYK2 Kinase
PubMed: 34224773
DOI: 10.1016/j.jaad.2021.06.869 -
Journal of Cellular and Molecular... Oct 2023Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic...
Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic targets are required. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) contributes to tumourigenesis and immune evasion in several cancers; however, its biological function in BC remains unknown. This study aimed to investigate the expression, prognostic value and protumoural function of MTHFD2 in BC and elucidate the mechanism of programmed death-ligand 1 (PD-L1) upregulation by MTHFD2. An analysis using publicly available databases revealed that a high MTHFD2 expression was correlated with clinical features and a poor prognosis in BC. Furthermore, MTHFD2 promoted the growth, migration, invasion and tumourigenicity and decreased the apoptosis of BC cells in vivo and in vitro. The results obtained from databases showed that MTHFD2 expression was correlated with immune infiltration levels, PD-L1 expression, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The expression of MTHFD2, PD-L1 and JAK/STAT signalling pathway-related proteins increased after interferon gamma treatment and decreased after MTHFD2 knockdown. Moreover, addition of a JAK/STAT pathway activator partially reduced the effect of MTHFD2 knockdown on BC cells. Collectively, our findings suggest that MTHFD2 promotes the expression of PD-L1 through the JAK/STAT signalling pathway in BC.
Topics: Humans; B7-H1 Antigen; Signal Transduction; Janus Kinases; STAT Transcription Factors; Urinary Bladder Neoplasms
PubMed: 37480214
DOI: 10.1111/jcmm.17863 -
Frontiers in Immunology 2023Ischemia-reperfusion injury (IRI) is a common complication of surgery, which can cause rapid deterioration of the liver function, increase the risk of graft rejection,... (Review)
Review
Ischemia-reperfusion injury (IRI) is a common complication of surgery, which can cause rapid deterioration of the liver function, increase the risk of graft rejection, and seriously affect the prognosis of patients. The signal transducer and activator of transcription 3 (STAT3) protein has been implicated in pathogenesis of IRI. STAT3 influences the mitochondria through multiple pathways and is also involved in apoptosis and other forms of programmed cell death. STAT3 is associated with Janus kinase (JAK), phosphoinositide-3 kinase (PI3K), and heme oxygenase-1 (HO-1) in liver IRI. The STAT3 pathway plays a dual role in IRI as it can also regulate lipid metabolism which may have potential for treating IRI fatty liver. In this review, we summarize research on the function of STAT3 in liver IRI to provide references for its application in the clinic.
Topics: Humans; STAT3 Transcription Factor; Signal Transduction; Liver; Reperfusion Injury; Janus Kinases
PubMed: 36761734
DOI: 10.3389/fimmu.2023.1066222