Breaking down the cellular responses to type I interferon neurotoxicity in the brain

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Фев. 3, 2023

Since their original discovery, type I interferons (IFN-Is) have been closely associated with antiviral immune responses. However, biological functions go far beyond this role, balanced IFN-I activity being critical to maintain cellular and tissue homeostasis. Recent findings uncovered a darker side of IFN-Is whereby chronically elevated levels induce devastating neuroinflammatory neurodegenerative pathologies. The underlying causes these ‘interferonopathies’ are diverse include monogenetic syndromes, autoimmune disorders, as well chronic infections. prominent involvement the CNS in disorders indicates particular susceptibility brain cells toxicity. Here we will discuss current knowledge how mediate neurotoxicity by analyzing cell-type specific responses CNS, secondly, exploring spectrum neurological arising from increased IFN-Is. Understanding nature is crucial fundamental step towards development new therapeutic strategies for interferonopathies.

Язык: Английский

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Tryptophan degradation as a systems phenomenon in inflammation – an analysis across 13 chronic inflammatory diseases

EBioMedicine, Год журнала: 2024, Номер 102, С. 105056 - 105056

Опубликована: Март 11, 2024

Язык: Английский

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TREX1 cytosolic DNA degradation correlates with autoimmune disease and cancer immunity

Clinical & Experimental Immunology, Год журнала: 2023, Номер 211(3), С. 193 - 207

Опубликована: Фев. 6, 2023

The N-terminal domain of Three Prime Repair Exonuclease 1 (TREX1) is catalytically active and can degrade dsDNA or ssDNA in the cytosol, whereas C-terminal primarily involved protein localization. TREX1 deficiency induces cytosolic DNA accumulation as well activation cGAS-STING-IFN signaling pathway, which results tissue inflammation autoimmune diseases. Furthermore, expression cancer immunity be adaptively regulated to promote tumor proliferation, making it a promising therapeutic target.

Язык: Английский

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Potential Use of Janus Kinase Inhibitors in the Treatment of Systemic Lupus Erythematosus

Journal of Inflammation Research, Год журнала: 2023, Номер Volume 16, С. 1471 - 1478

Опубликована: Апрель 1, 2023

Abstract: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with unclear pathogenesis. One characteristic of SLE pro-inflammatory and anti-inflammatory cytokine imbalance. Janus kinase (JAK) an intracellular non-receptor tyrosine essential for many signaling pathways. Dysregulation the JAK/signal transduction transcriptional activator (STAT) pathway important process in Targeting JAK/STAT proteins can simultaneously block functions multiple cytokines. Current treatment non-specific corticosteroids immunosuppressants cause adverse reactions. Therefore, treatments designed to control specific molecular targets are desirable. JAK inhibitors (JAKis) potential rheumatic diseases; however, use targeted pathways treat remains challenge, its efficacy has not been determined. JAKis have shown positive results reducing glucocorticoids and/or SLE. currently undergoing several clinical trials expected be next stage inhibition through may improve traditional strategies Keywords: systemic erythematosus, kinase, pathway,

Язык: Английский

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Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus (jSLE)

Molecular and Cellular Pediatrics, Год журнала: 2023, Номер 10(1)

Опубликована: Авг. 9, 2023

Systemic lupus erythematosus (SLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Approximately 15-20% of SLE patients develop the during childhood or adolescence (juvenile-onset SLE/jSLE). Patients jSLE exhibit more variable severe when compared to disease-onset adulthood. Neuropsychiatric (NP) involvement clinically heterogenous potentially complication. Published reports on incidence prevalence NP-jSLE are scarce, exact pathophysiology poorly understood.This manuscript provides review existing literature, suggesting NP in 13.5-51% patients. Among affecting CNS, we propose two main subgroups: (i) chronic progressive, predominantly type 1 interferon-driven form that responds currently used treatments, (ii) an acutely aggressive usually presents early may be primarily mediated by auto-reactive effector lymphocytes. While this hypothesis requires tested large collaborative international cohort studies, it offer future patient stratification individualised care.

Язык: Английский

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Intricating connections: the role of ferroptosis in systemic lupus erythematosus

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 4, 2025

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease with multiple tissue damage. However, the pathology remains elusive, effective treatments are lacking. Multiple types of programmed cell death (PCD) implicated in SLE progression have recently been identified. Although ferroptosis, an iron-dependent form death, has numerous pathophysiological features similar to those SLE, such as intracellular iron accumulation, mitochondrial dysfunction, lipid metabolism disorders concentration damage associated-molecular patterns (DAMPs), only few reports demonstrated that ferroptosis involved role pathogenesis continues be neglected. Therefore, this review elucidates potential intricate relationship between provide reliable theoretical basis for further research on SLE.

Язык: Английский

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PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(5)

Опубликована: Фев. 19, 2025

Type I IFN (IFN-I) induce hundreds of antiviral genes as well negative regulators that limit IFN-I signaling. Here, we investigate the family 16 PARPs and find 11 are ISGs, which 8 inhibit production. PARP7 is most potent feedback regulator Using Parp7−/− Parp7H532A/H532A mice, show loss leads to systemic autoimmunity characterized by splenomegaly increased autoantibodies inflammatory cytokines. also results in perivascular immune infiltration lung forms tertiary lymphoid structures. Mechanistically, inhibits multiple innate pathways a cell-intrinsic MARylation-dependent manner. interacts with IRF3 through catalytic domain disrupts IRF3:CBP/p300 transcriptional holocomplex required for Irf3−/− or Irf3S1/S1 (transcription defective) Sting−/− rescues mouse disease. Together, our study reveals physiological functions production maintains homeostasis particularly lung.

Язык: Английский

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Systemic lupus erythematosus and atherosclerosis: immune pathways and the uncharted territory of gut microbiota and metabolism

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 28, 2025

Patients with Systemic Lupus Erythematosus (SLE) are significantly more susceptible to atherosclerosis, which may elevate their mortality risk. The review explores recent understandings of the origins and remedies for atherosclerosis associated SLE. Our focus is particularly on consequences immune system disparities, interruptions in intestinal bacteria, metabolic complications. influence SLE extends past usual risk elements, including processes specific disease. list encompasses excessive cell activity, production autoantibodies, inflammatory responses. A variety therapies linked encompass cholesterol-lowering medications, anti-inflammatory drugs, suppressors, antimalarials, interferon treatments, NET inhibitors, methods aimed at T B-cells. However, existing research has its shortcomings, necessitating additional clinical trials ascertain efficacy security these therapies. direct interactions among SLE, gut microbiota, metabolism, underexplored, presenting innovation opportunities. Research into microbial strains metabolites’ effects responses progression patients needed. Such could uncover novel therapeutic targets biomarkers, advancing prevention treatment strategies cardiovascular

Язык: Английский

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Novel heterozygous TREX1 mutation in a juvenile systemic lupus erythematosus patient with severe cutaneous involvement treated successfully with Jak-inhibitors: a case report

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Дек. 6, 2023

Juvenile systemic lupus erythematosus (jSLE) is a complex inflammatory autoimmune disorder. In the last decades, genetic factors and activation pathways have been increasingly studied to understand their potential pathogenetic role better. Genetic transcriptional abnormalities directly involved in type I interferon (IFN) signaling cascade identified through family-based genome-wide association studies. IFNs trigger that initiate gene transcription of IFN-stimulated genes JAK1, TYK2, STAT1, STAT2. Thus, use therapies target IFN pathway would represent formidable advance SLE. It well known JAK inhibitors real for treatment rheumatic diseases, but efficacy SLE remains be elucidated. We report case 13-year-old girl affected by jSLE, carrying novel heterozygous missense variant on Three prime Repair EXonuclease 1 ( TREX1 ), successfully treated with baricitinib top mofetil mycophenolate. The plays an important DNA damage repair, its mutations associated overproduction interferon. This underlines translational research identifying rare diseases optimize treatment.

Язык: Английский

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Association of the STAT4 Gene rs7574865 Polymorphism with IFN-γ Levels in Patients with Systemic Lupus Erythematosus

Genes, Год журнала: 2023, Номер 14(3), С. 537 - 537

Опубликована: Фев. 21, 2023

STAT4 plays an important role in disease activity SLE patients. particles have the capacity to activate transcription of genes associated with production TH1 and Th17 lymphocytes, a greater predominance on IFN-γ IL-17A. The presence variants has major impact generation autoimmunity. However, there are few studies evaluating these proinflammatory cytokines such as Methods—A case–control study was carried out 206 Mexican mestizo patients residing Western Mexico diagnosis group 80 without autoimmune diseases captured determine cut-off point for high levels. In this study, levels were considered cases (cut-off > 15.6 pg/mL), normal controls ≤ pg/mL). Disease identified from systemic lupus erythematosus index (SLEDAI). For determination IFN-γ, IL-12, IL17A, commercial ELISA kits used. Genotyping rs7574865 (G T) performed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. Results—The had median age 45 years range duration 4 18 years; 45.6% having activity. sample, we prevalence 35.4%. higher genotype TT than GG. We found that conferred risk when compared GG GT genotypes. Conclusions—In polymorphic gene polymorphism is increased IFN-γ. its strength association weak, so complementary needed evaluate

Язык: Английский

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