N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis

Kuley, Runa; Stultz, Ryan D.; Duvvuri, Bhargavi; Wang, Ting; Fritzler, Marvin J.; Hesselstrand, Roger; Nelson, J. Lee; Lood, Christian

doi:10.3389/fimmu.2021.785275

Cited by 23 publications

(17 citation statements)

References 53 publications

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“…These results are in agreement with the hypothesis that GI inflammation may be an early manifestation of SSc [ 6 ] Calprotectin has been established as a marker of inflammation and neutrophil activation in several diseases, including SSc [ 17 ]. Recently, calprotectin dependent neutrophil mediated inflammation has been described in relation to disease pathogenesis in SSc, further promoting the rationale of exploring calprotectin as biomarker in SSc [ 18 ]. Our study are in line with these reports, as 35 out of 92 patients exhibited elevated levels of F-cal.…”

Section: Discussionmentioning

confidence: 99%

Elevated fecal levels of the inflammatory biomarker calprotectin in early systemic sclerosis

et al. 2022

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Knowledge on gastrointestinal manifestations in early systemic sclerosis (SSc) is limited. We have investigated gastrointestinal inflammation in SSc at the time of diagnosis using the inflammatory biomarker Fecal calprotectin (F-cal). Consecutive patients with suspected SSc were characterized in relation to the 2013 classification criteria for SSc and classified as SSc or SSc-like disease. F-cal levels were measured with a polyclonal ELISA (Calpro A/S, Lysaker, Norway) and levels above 50 µg/g were considered elevated. F-cal levels were compared to those of control subjects without rheumatic disease. Of 137 patients with suspected SSc, 92 were classified as SSc and 45 as SSc-like disease. Median (interquartile range) disease duration among the SSc participants was 2.5 (1.2, 4.6) years. A substantial proportion of participants classified as SSc (35/92, 38%) and SSc-like disease (14/45, 31%) exhibited elevated F-cal compared to the control group (3/41, 7.3%; p < 0.001 and p = 0.007, respectively). Elevated F-cal was associated with proton pump inhibitor usage (OR 7.14; 95% CI 2.56–29.93; p < 0.001). We conclude that elevated F-cal is present in a subgroup of patients with SSc at the time of diagnosis, suggesting that that GI inflammation may be present in this patient group early in the disease course. F-cal did not exhibit potential to differentiate SSc from SSc-like disease.

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Section: Discussionmentioning

confidence: 99%

Elevated fecal levels of the inflammatory biomarker calprotectin in early systemic sclerosis

et al. 2022

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“…We, and others, have recently highlighted an important role for N-formylated methionine peptides in several rheumatic diseases, including scleroderma, rheumatoid arthritis, and vasculitis, 82 – 84 with elevated levels of N-formyl methionine peptides in peripheral blood promoting neutrophil activation through FPR1-mediated pathways. However, whether mitochondrial-derived N-formyl methionine would be released by damaged/dying muscle tissue in myopathies, and cause local and/or systemic inflammation, has not yet been studied.…”

Section: Mitochondrial-mediated Inflammationmentioning

confidence: 97%

The Emerging Role of Mitochondrial Dysfunction in the Pathogenesis of Idiopathic Inflammatory Myopathies

Gonzalez-Chapa¹,

Macêdo²,

Lood³

2023

Rambam Maimonides Med J

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Increasing evidence points towards mitochondria as crucial players in the initiation and progression of auto-immune and degenerative disorders, to which impaired cell metabolism is but a facet of the subjacent etiopathogenesis. This review aims to introduce the reader to essential concepts of mitochondrial abnormalities in idiopathic inflammatory myopathy (IIM), underscoring inclusion-body myositis and dermatomyositis. Far surpassing the initial simplistic view of being responsible for energy generation, mitochondria have gathered attention regarding their role in inflammatory processes, being able to fuel autoimmunity, as shown by the presence of anti-mitochondrial antibodies (AMAs) in up to 10% of IIM patients. As cellular respiration takes place, mitochondrial metabolites might help to shape the pro-inflammatory milieu in affected muscle, beyond generating reactive oxygen species, which are well-recognized inducers of damage-associated molecular patterns. A series of mitochondrial components might facilitate the sterile activation of pro-inflammatory cells and the production of several cytokines responsible for enhancing auto-immune responses. Marked variation in the mitochondrial genome has also been reported in IIM patients. As such, we summarize key historical and recent advances linking aberrations and instabilities of mitochondrial DNA to impaired muscle function. Besides discussing mitochondrial dysfunction as an essential part of IIM development, we also highlight possible associations between presence of AMAs and a particular phenotype of IIM, with its own characteristic clinical and radiological pattern. Finally, we present promising treatment approaches targeting mitochondria, while briefly discussing experimental models for gaining deeper insight into the disease process, and ultimately leading to novel drug development.

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“…Senescent neutrophils express high levels of CXCR4 and become responsive to SDF-1a [22]. Although neutrophils from SSc patients have been shown to harbour functional defects [23], other studies suggest that NET formation is augmented in these SSc [24,25]. It is thus difficult to assess the contribution of neutrophil senescence in SSc pathogenesis.…”

Section: Inflammation-innate Immunitymentioning

confidence: 99%

Role of cellular senescence in the pathogenesis of systemic sclerosis

Tsou

Shi

Varga

2022

Current Opinion in Rheumatology

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Purpose of reviewSystemic sclerosis (SSc) is a chronic rheumatic disease that is characterized by immune activation, vasculopathy and fibrosis of the skin and internal organs. It has been proposed that premature onset of ageing pathways and associated senescent changes in cells contribute to the clinical and pathological features of SSc. The aim of this review is to critically review recent insights into the involvement of cellular senescence in SSc.Recent findingsCellular senescence plays a critical role in SSc pathogenesis, particularly involving endothelial cells and fibroblasts. Immunosenescence could also contribute to SSc pathogenesis by direct alteration of cellular functions or indirect promotion of defective immune surveillance. Molecular studies have shed some light on how cellular senescence contributes to fibrosis. Recent and planned proof-of-concept trials using senotherapeutics showed promising results in fibrotic diseases, including SSc.SummaryThere is increasing evidence implicating cellular senescence in SSc. The mechanisms underlying premature cellular senescence in SSc, and its potential role in pathogenesis, merit further investigation. Emerging drugs targeting senescence-related pathways might be potential therapeutic options for SSc.

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N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis

Cited by 23 publications

References 53 publications

Elevated fecal levels of the inflammatory biomarker calprotectin in early systemic sclerosis

Elevated fecal levels of the inflammatory biomarker calprotectin in early systemic sclerosis

The Emerging Role of Mitochondrial Dysfunction in the Pathogenesis of Idiopathic Inflammatory Myopathies

Role of cellular senescence in the pathogenesis of systemic sclerosis

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