Type 1 interferon activation in systemic sclerosis: a biomarker, a target or the culprit

Kakkar, Vishal; Assassi, Shervin; Allanore, Yannick; Kuwana, Masataka; Denton, Christopher P.; Khanna, Dinesh; Galdo, Francesco Del

doi:10.1097/bor.0000000000000907

Cited by 19 publications

(38 citation statements)

References 94 publications

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“…Interestingly, several lines of evidence point towards shared physiopathological features between, SLE and SSc. Efferocytic defects could indeed lead in both pathologies to IFN signatures observed in several SSc patients 23 . Interestingly, LAP has been involved in the limitation of IFN signaling after engulfment of dead cells 12 .…”

Section: Results Discussionmentioning

confidence: 99%

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Frenger,

Lucas,

Petitdemange

et al. 2024

Preprint

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Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called “noncanonical” autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly inATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment.Key messagesPolymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLEWhile autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SScWe show here that autophagy is comparable between PBMCs from patients and matched controlsWe find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patientsAs LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation

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Section: Results Discussionmentioning

confidence: 99%

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Frenger,

Lucas,

Petitdemange

et al. 2024

Preprint

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“…Serum IFN-γ levels were found to be higher in SSc when compared to controls and to be associated, among patients, with PAH [ 150 ]. Moreover, a higher type 1 IFN signature at both transcript and protein levels in whole blood or plasma of SSc patients has been found to correlate with more severe vascular manifestations [ 228 ].…”

Section: Cytokinesmentioning

confidence: 99%

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

Fioretto

Rosa

Matucci‐Cerinic

et al. 2023

IJMS

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Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease.

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“…Systemic Sclerosis (SSc) is an auto-immune disease which initially presents in the hands and feet of patients and can variably progress to affect most internal organs including the gastrointestinal tract, heart and lungs. The tissue fibrosis is associated with a deregulated activation of type-1 interferon (IFN) signalling (1,2) which leads (through activation of cytokines such IL-6 and TGF-β) to activation of myofibroblasts. Recent work from our group has shown the chloride intracellular channel 4 (CLIC4) is a mediator of SSc myofibroblast activation (3).…”

Section: Introductionmentioning

confidence: 99%

Chloride intracellular channel 4 (CLIC4) is a global regulator of type 1 interferon signaling in Systemic Sclerosis (SSc) epithelial cells

Wasson,

Dibb,

Caballero-Ruiz

et al. 2024

Preprint

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ObjectivesSystemic sclerosis (SSc) is an autoimmune disease in which an immune-related injury induces fibrosis of the skin, progressing to affect the internal organs in the most serve cases. Type 1 interferon (IFN) signaling plays a major role in SSc disease progression. We have previously shown the chloride intracellular channel 4 (CLIC4) is upregulated in SSc skin fibroblasts and plays an important role in SSc fibrosis. In this study we investigated the role of CLIC4 in SSc keratinocyte biology.Methodshealthy (HC) and SSc skin biopsies were analysed by immunohistochemistry for the expression of CLIC4. The skin keratinocyte cell line Hacats was stimulated with a range of type 1 IFN signaling agonists (POLY I:C, POLY dA:Dt, ODN 2216 and IFN-α). CLIC4 was inhibited with the chloride channel inhibitors NPPB and IAA-94 or siRNA. Conditioned media from HC or SSc fibroblasts was employed for indirect co-culture of Hacats and HUVECs.ResultsSSc skin biopsies showed high levels of CLIC4 in SSc skin fibroblasts, keratinocytes and endothelial cells compared to HC. Co-culture of Hacats and Huvecs with SSc fibroblast media induced CLIC4 expression. CLIC4 played an important role in type 1 IFN signalling in keratinocytes. Inhibition of CLIC4 blocked TLR3, TLR9 and cGAS mediated activation of the type 1 IFN signaling pathway. Additionally, inhibition of CLIC4 prevented SSc fibroblast media from inducing a type 1 IFN response in keratinocytes.ConclusionsThe data presented in this study suggests CLIC4 is a global regulator of type 1 IFN signalling in SSc epithelial cells.Key MessagesWhat is already knownSSc disease progression is driven in part by a Type 1 IFN signature and CLIC4 has previously been implicated in SSc fibroblast activation.What this study addsWe show for the first time CLIC4 is a regulator of type 1 interferon signalling in epithelial cells and plays an important role in the signalling found in SSc skin.How this study might affect researchTargeting CLIC4 in the context of SSc may disrupt the fibrosis and inflammation associated with SSc.

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Type 1 interferon activation in systemic sclerosis: a biomarker, a target or the culprit

Cited by 19 publications

References 94 publications

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

Chloride intracellular channel 4 (CLIC4) is a global regulator of type 1 interferon signaling in Systemic Sclerosis (SSc) epithelial cells

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