Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma

Yaseen, Bodoor; Lopez, Henry; Taki, Zeinab; Zafar, Sara; Rosario, Henrique; Abdi, Bahja Ahmed; Vigneswaran, Shivanee; Xing, Fiona; Arumalla, Nikita; Black, Simon; Ahmad, Shahreen; Kumar, Kimti; Gul, Rabia; Scolamiero, Laura; Morris, Sian; Bowman, Alex; Stainer, Anna; Rice, Alexandra; Stock, Carmel; Renzoni, Elisabetta; Denton, Christopher P.; Venturini, Cristina; Brown, Max; O’Reilly, Steven; Stratton, Richard

doi:10.1093/rheumatology/keaa195

Cited by 36 publications

(27 citation statements)

References 34 publications

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“…In addition, whole lung transcriptome analysis revealed a decrease in the expression of ECM-related genes, which thus supports the role of IL-31/IL-31RA in lung fibrosis. Our findings align with a recent publication demonstrating that in scleroderma IL-31 contributes to skin fibrosis; in this study, a sub-cutaneous mini-pump was implanted in the skin to deliver IL-31 (21). We assessed changes in tissue inflammation using H&E staining of lung section from wildtype and IL-31RA knout-out mice treated with saline and bleomycin (Supplementary Figure 5).…”

Section: Discussionsupporting

confidence: 86%

“…Recent studies have shown elevated levels of IL-31 in patients with AD or asthma and these levels have been correlated with disease severity (19,20). Importantly, a recent published study suggests a significant increase in IL-31 levels in plasma, fibrotic skin, and lung lesions of patients with scleroderma compared to healthy controls (21). Similar findings have been reported during bleomycin-induced pulmonary fibrosis and also virus-induced liver fibrosis (22,23).…”

Section: Introductionsupporting

confidence: 56%

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The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

et al. 2021

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Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionsupporting

confidence: 56%

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

et al. 2021

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“…In addition, whole lung transcriptome analysis revealed a decrease in the expression of ECM-related genes, which supports the role of IL-31/IL-31RA in lung fibrosis. Our findings align with a recent publication demonstrating that in scleroderma IL-31 contributes to skin fibrosis; in this study, a subcutaneous mini-pump was implanted in the skin to deliver IL-31 [41]. Together, these studies (which was not certified by peer review) is the author/funder.…”

Section: Discussionsupporting

confidence: 88%

The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis

Yombo

Odayar

Gupta

et al. 2020

Preprint

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Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Multiple Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 TH2 T cells, but its signaling receptor called IL-31RA has been shown predominately expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including ECM- and epithelial cell-associated gene networks. Furthermore, the lungs of IPF showed an elevated expression of IL-31 when compared to control subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. In summary, therapeutic targeting of the IL-31-IL-31RA axis could be beneficial in pulmonary fibrosis and has translational benefits specifically by preventing collagen deposition and improving lung function.

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“…IL-31 also appears to mediate vascular inflammation and contribute to the aforementioned vasculopathy. 114 IL-31Ra seems to be upregulated in surrounding tissue cells during the SSc disease state, showing that this axis is likely stimulated in an aberrant manner. 115 IL-33 has been studied as a disease marker in SSc.…”

Section: Discussionmentioning

confidence: 97%

Interrelationship and Sequencing of Interleukins4, 13, 31, and 33 – An Integrated Systematic Review: Dermatological and Multidisciplinary Perspectives

Tatu¹,

Nadasdy²,

Arbune³

et al. 2022

JIR

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The interrelations and sequencing of interleukins are complex (inter)actions where each interleukin can stimulate the secretion of its preceding interleukin. In this paper, we attempt to summarize the currently known roles of IL-4, IL-13, IL-31, and IL-33 from a multi-disciplinary perspective. In order to conduct a comprehensive review of the current literature, a search was conducted using PubMed, Google Scholar, Medscape, UpToDate, and Key Elsevier for keywords. The results were compiled from case reports, case series, letters, and literature review papers, and analyzed by a panel of multi-disciplinary specialist physicians for relevance. Based on 173 results, we compiled the following review of interleukin signaling and its clinical significance across a multitude of medical specialties. Interleukins are at the bed rock of a multitude of pathologies across different organ systems and understanding their role will likely lead to novel treatments and better outcomes for our patients. New interleukins are being described, and the role of this inflammatory cascade is still coming to light. We hope this multi-discipline review on the role interleukins play in current pathology assists in this scope.

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Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma

Cited by 36 publications

References 34 publications

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis

Interrelationship and Sequencing of Interleukins4, 13, 31, and 33 – An Integrated Systematic Review: Dermatological and Multidisciplinary Perspectives

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