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Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts. [ABSTRACT FROM AUTHOR]

Systemic sclerosis is an autoimmune connective tissue disease which is characterised by vascular perturbations, inflammation, and fibrosis. Although huge progress recently into the underlying molecular pathways that are perturbed in the disease, currently no therapy exists that targets the fibrosis element of the disease and consequently there is a huge unmet medical need. Emerging studies reveal new dimensions of complexity, and multiple aberrant pathways have been uncovered that have shed light on disturbed signalling in the disease, primarily in inflammatory pathways that can be targeted with repurposed drugs. Pre-clinical animal models using these inhibitors have yielded proof of concept for targeting these signalling systems and progressing to clinical trials. This review will examine the recent evidence of new perturbed pathways in SSc and how these can be targeted with new or repurposed drugs to target a currently intractable disease. [ABSTRACT FROM AUTHOR]

Summary: Interleukin-11 is a cytokine from the IL-6 family of cytokines that includes IL-6 and oncostatin-M. Initially described for its role in platelet generation, it is now appreciated that this cytokine has multiple functions. Recently it has been found that IL-11 is critical in fibrosis in multiple different organ systems and systemically as in the autoimmune disease systemic sclerosis. Animal models of fibrosis have determined that animals with IL-11 receptor deletions have retarded fibrosis and that in wild-type animals IL-11 is found at the organ of fibrosis. Recent evidence suggests that IL-11 may be a master regulator of fibrosis regardless of end target organ. With the development of neutralizing antibodies targeting the cytokine in pre-clinical models this could be a possible therapeutic, in a disease in which no specific therapies exist. This review appraises the evidence of the role of IL-11 in tissue fibrosis, its signalling properties, and therapeutic targeting. The review ends with an appraisal of indications for which IL-11 modulation is targeted. IL-11 is a key IL-6 family cytokine that has recently been associated with tissue fibrosis. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is elevated inflammation, aberrant cytokine expression, and subsequent fibrosis. Interleukin‐11 (IL‐11) is a recently described profibrotic cytokine that can mediate fibrosis in the heart, lungs, and skin and is upregulated by transforming Growth Factor‐β (TGF‐β1). The objective of this study was to quantify the serum levels of IL‐11 in early diffuse SSc patients. Also, if IL‐11 could regulate the alarmin IL‐33 in dermal fibroblasts was quantified. Early diffuse SSc patient sera was isolated and IL‐11 was quantified by specific commercial ELISA compared to healthy control (n = 17). Healthy dermal fibroblasts were cultured in vitro and then serum starved and incubated with or without recombinant IL‐11. At specific early and late time points the supernatant was quantified for the alarmin IL‐33 by specific ELISA. In early diffuse SSc patients it was demonstrated that they have elevated IL‐11 in their sera. In a subgroup of SSc patients with interstitial lung disease (ILD) this elevation was particularly pronounced compared to those devoid of fibrotic lung disease. In vitro incubation of healthy dermal fibroblasts led to a significant induction of IL‐33 cytokine release into the cell media. IL‐11 is a profibrotic cytokine that is elevated in early diffuse SSc and is particularly elevated in those with ILD. This suggests that IL‐11 could be a possible biomarker of ILD in SSc. It was also found that IL‐11 led to release of the cytokine alarmin IL‐33 in fibroblasts at earlier time points but not late time points, suggesting early stimulation elicits an inflammatory response in the local microenvironment but prolonged stimulation leads to fibrosis. [ABSTRACT FROM AUTHOR]

SSc is an autoimmune disease that has features of vascular abnormalities, inflammation and skin and lung fibrosis. Toll-like receptors (TLRs) are sentinel receptors that serve to recognize pathogens or internal danger signals leading to downstream signalling pathways that ultimately lead to inflammation and modification of adaptive immunity. Inflammation and fibrosis appear intricately connected in this disease and TLR ligation on fibroblasts can directly activate these cells to produce copious amounts of collagen, a hallmark of disease. The presence of damage-associated molecular patterns in association with fibrosis has been highlighted. Given their prominent role in disease, this review discusses the evidence of their expression and role in disease pathogenesis and possible therapeutic intervention to mitigate fibrosis. [ABSTRACT FROM AUTHOR]

Gremlin-1 is part of the TGF-β superfamily and is a BMP antagonist that blocks BMP signalling to precisely control BMP gradients. Gremlin-1 is primarily involved in organogenesis and limb patterning however, has recently been described as being involved in fibrotic diseases. Initially described as a key factor involved in diabetic kidney fibrosis due to being induced by high glucose, it has now been described as being associated with lung, liver, eye, and skin fibrosis. This suggests that it is a key conserved molecule mediating fibrotic events irrespective of organ. It appears that Gremlin-1 may have effects mediated by BMP-dependent and independent pathways. The aim of this review is to evaluate the role of Gremlin-1 in fibrosis, its mechanisms and if this can be targeted therapeutically in fibrotic diseases, which currently have very limited treatment options and are highly prevalent. [ABSTRACT FROM AUTHOR]

Objectives Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. Methods We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. Results In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK. Conclusions These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc. [ABSTRACT FROM AUTHOR]

Senescence is associated with multiple morbidities and therapeutic targeting of these cells is a key aim. In a recent study, Katsuumi et al. found that targeting sodium-glucose co-transporter 2 (SGLT2) promoted immune clearance of senescent cells via programmed cell death-1 ligand (PD-L1) suppression, thus promoting immunosurveillance. This could have profound implications for many age-related diseases, including cancer and frailty., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Systemic sclerosis is an autoimmune connective tissue disease in which there is activation of the immune system, vascular disease and fibrosis. Activation of quiescent fibroblasts to myofibroblasts is key to disease pathogenesis. Gremlin-1 is a bone morphogenetic protein antagonist which is important in development and we recently reported in skin fibrosis. The aim of this study was to determine the serum circulating levels of Gremlin-1 in early diffuse systemic sclerosis., Methods: Twenty-one early diffuse systemic sclerosis patients (less than 2 years from first non-Raynaud's symptom) were included and age and sex-matched healthy controls. Serum was isolated from blood and measured with a specific enzyme-linked immunoassay for Gremlin-1. Clinical variables were also measured., Results: Significantly elevated Gremlin-1 was found in sera of early diffuse systemic sclerosis patients ( p < 0.001). In patients with interstitial lung disease, this compared to systemic sclerosis without evidence of interstitial lung disease, Gremlin-1 was significantly elevated ( p < 0.0007). A correlation was found between circulating Gremlin-1 and modified Rodnan Skin Score, albeit weak., Discussion: In early diffuse systemic sclerosis patients, elevated Gremlin-1 is found in serum. This is particularly prominent in systemic sclerosis-associated interstitial lung disease. This suggests that Gremlin-1 may be a biomarker for systemic sclerosis interstitial lung disease., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2021.)