Elevated interleukin‐11 in systemic sclerosis and role in disease pathogenesis

Abstract

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.

Commensal microbiome dysbiosis elicits interleukin-8 signaling to drive fibrotic skin disease

“…We found significant differences between them. Surprisingly, IL-8-treated samples showed decreased expression of genes involved in fibrotic events, such as COL4A1 , COL10A1 ( 39 , 40 ), and IL11 ( 41–44 ). However, it enhances canonical signaling driving fibrotic programs, as evidenced by up-regulated TGFβR3 and SMAD3 ( 45 , 46 ) ( SI Appendix , Fig.…”

Cytotoxic and Immunomodulatory Effects of Hypericin as a Photosensitizer in Photodynamic Therapy Used on Skin Cell Cultures

“…IL-11 has also been shown to stimulate the release of the alarm cytokine IL-33 in fibroblasts, triggering an inflammatory response in the local microenvironment. Unfortunately, such long-term stimulation ultimately leads to fibrosis, playing an important role in diseases such as systemic sclerosis (SSc) [ 56 , 57 ]. Extensive clinical trials remain necessary to confirm the efficacy of rhIL-11 as an anti-inflammatory agent in psoriasis patients [ 46 ].…”

Understanding interleukin 11 as a disease gene and therapeutic target

“…The scientific community working on lung fibrosis was quick to embrace the idea that IL11 is an important pro-fibrotic factor and a number of publications have validated and extended findings: 2020, IL11/ERK signalling is important for senescence of lung cells [ 68 ] and fibroblast-specific expression of IL11 causes lung fibro-inflammation [ 140 ]; 2021, IL11 expression is associated with lung fibrosis in patients with rheumatoid arthritis [ 153 ], replication of IL11 up-regulation and its effects in bleomycin injury and HPS [ 154 ]; 2022, nanoparticle delivery of siRNA against Il11 reduces lung fibrosis in the bleomycin mouse model [ 155 ], IL11 contributes to pulmonary artery remodelling and fibrosis in pulmonary hypertension [ 90 ], therapeutic targeting of IL11 reduces lung fibro-inflammation due to silica particle inhalation [ 156 ]; 2023, anti-IL11 reduces emphysematous disease in a mouse model of Marfan syndrome [ 157 ], IL11 disrupts alveolar epithelial cell repair functions by causing EMT [ 103 , 104 ], IL11 is elevated in interstitial lung disease in systemic sclerosis [ 158 , 159 ] and IL11 contributes to lung fibrosis in patients with SARS-COV-2 [ 160 , 161 ].…”

“…IL11 is also one the the most highly up-regulated genes in both resident and migratory skin fibroblasts from patients with SSc [ 183–185 ]. IL11 serum levels are elevated in SSc and are most increased in patients with SSc-ILD [ 158 , 159 , 186 ]. Of note, IL6 is also increased in SSc fibroblasts and anti-IL6R therapy was recently approved for the treatment of SSc-ILD, although this approach does not improve SSc skin disease [ 187 ].…”