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Interleukin-17 pathways in systemic sclerosis-associated fibrosis

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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.

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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

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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.

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Correspondence to Vikas Agarwal.

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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.

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Ahmed, S., Misra, D.P. & Agarwal, V. Interleukin-17 pathways in systemic sclerosis-associated fibrosis. Rheumatol Int 39, 1135–1143 (2019). https://doi.org/10.1007/s00296-019-04317-5

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