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Rheumatology International

, Volume 39, Issue 7, pp 1135–1143 | Cite as

Interleukin-17 pathways in systemic sclerosis-associated fibrosis

  • Sakir Ahmed
  • Durga Prasanna Misra
  • Vikas AgarwalEmail author
Review

Abstract

Fibrosis is unregulated tissue repair that may cause impairment of organ function, especially in end-organ damage. Systemic sclerosis (SSc) is the prototype systemic fibrosing disorder. Classical targets for fibrosis in SSc like transforming growth factor Beta (TGF-β), Interleukin-6 (IL-6), and multiple tyrosine kinases, have not yielded therapeutic benefit. There is multitude of evidence from across different tissues like the heart, lung, skin, liver, colon, and, to some extent, the kidney, that interleukin-17 (IL-17) and its downstream pathways are strongly associated with the initiation and propagation of fibrosis. Data from scleroderma patients, as well as from animal models of SSc, mirror these findings. Interestingly, hitherto unknown to be related to IL-17, newer molecules like Programmed Death-protein1 (PD-1), the phosphatase SHP2, along with known signal transducers like signal transducer and activator of transcription (STAT3), have been recently shown to be involved in the pathogenesis of fibrosis. Related molecules include the intracellular signalling molecules Ras/Erk, mammalian target organ of rapamycin (mTOR), and complement components. The biology of these pathways has not yet been fully elucidated to predict regulatory mechanisms, redundancies, and potential off-target effects. All these need to be better understood in the context of each other, in an effort to arrive at the optimal target to modulate fibrosis.

Keywords

Interleukin 17 T helper 17 STAT3 Fibrosis Systemic sclerosis 

Abbreviations

BAFF

B-cell activating factor

C3a

Complement component 3a

CCl4

Carbon tetrachloride

CCL5

Chemokine ligand 5

CTGF

Connective tissue growth factor

EMT

Epithelial-to-mesenchymal transition

ERK 1/2

Extracellular signal-regulated kinase 1/2

FGFR2

Fibroblast growth factor receptor 2

γδ T-cells

Gamma delta T cells

G-CSF

Granulocyte colony-stimulating factor

GD15

Growth/differentiation factor 15

GVHD

Graft versus host disease

IL

Interleukin

ITIM

Immunoreceptor tyrosine-based inhibitory motifs

MAPK

Mitogen-activated protein kinase

MMP-1

Matrix metalloproteinase-1

mRNA

Messenger ribonucleic acid

NET

Neutrophil extracellular traps

NLR

NOD-like receptor

NLRP-3

NOD-like receptor (NLR) family pyrin containing domain 3

NF-κB

Nuclear factor kappa B

PD-1

Programmed cell death 1

RANKL

Receptor activator of nuclear factor kappa B ligand

SH2

Src homology 2

SSc

Systemic sclerosis

Stat-3

Signal transduction and activator of transcription-3

TGF-β

Transforming growth factor beta

Th

T helper cell

TLR

Toll like receptor

TNF-α

Tumor necrosis factor alpha

Treg

T regulatory cell

TSA

Trichostatin A

Tsk-1

Tight skin mouse 1

Notes

Author contributions

The conception and design of the study, acquisition of data, analysis and interpretation of data—SA, DPM, VA. Drafting the article—SA; Revising it critically for important intellectual content—DPM, VA. Final approval of the version to be submitted—SA, DPM, VA. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved—SA, DPM, VA.

Funding

No funding was received for this study.

Compliance with ethical standards

Conflict of interest

Sakir Ahmed declares that he has no conflict of interest, including no relationship with pharmaceutical companies. Durga Prasanna Misra declares that he has no conflict of interest, including no relationship with pharmaceutical companies. Vikas Agarwal declares that he has no conflict of interest, including no relationship with pharmaceutical companies.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences (KIMS)KIIT UniversityBhubaneswarIndia
  2. 2.Department of Clinical Immunology and RheumatologySanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS)LucknowIndia

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