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Review
. 2020 Jun;24(11):5973-5983.
doi: 10.1111/jcmm.15259. Epub 2020 Apr 19.

Extracellular S100A4 as a key player in fibrotic diseases

Zhenzhen Li  1 , Yanan Li  2   3 , Shuangqing Liu  3 , Zhihai Qin  1   3
Affiliations
Review

Extracellular S100A4 as a key player in fibrotic diseases

Zhenzhen Li et al. J Cell Mol Med. 2020 Jun.

Abstract

Fibrosis is characterized by fibroblast activation, extracellular matrix (ECM) accumulation and infiltration of inflammatory cells that sometimes leads to irreversible organ dysfunction. Considerable evidence now indicates that inflammation plays a critical role in the initiation and progression of organ fibrosis. S100A4 protein, a ubiquitous member of the S100 family, has recently been discovered as a potential factor implicated in fibrotic diseases. S100A4 protein is released at inflammatory site and has a certain biological function to promote cell motility, invasion, ECM remodelling, autophagy and angiogenesis. In addition, extracellular S100A4 is also a potential causation of inflammatory processes and induces the release of cytokines and growth factors under different pathological conditions. Elevated S100A4 level in patients' serum closely correlates with disease activity in several fibrotic diseases and serves as a useful biomarker for diagnosis and monitoring disease progression. Analyses of knockout mouse models have identified a functional role of extracellular S100A4 protein in fibrotic diseases, suggesting that suppressing its expression, release or function might be a promising therapeutic strategy. This review will focus on the role of extracellular S100A4 as a key regulator of pro-inflammatory signalling pathways and its relative biological processes involved in the pathogenesis of fibrosis.

Keywords: Fibrosis; biomarker; damage-associated molecular pattern; extracellular S100A4; inflammation.

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Conflict of interest statement

The authors confirm that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Functions of extracellular S100A4 protein. S100A4 can be released into the extracellular space by fibroblasts, macrophages, lymphocytes and myeloid cells. The expression of extracellular S100A4 leads to increased phosphorylation of ERK1/2 and activation of NF‐κB through the RAGE‐dependent regulation, which is associated with cell motility, invasion, cell survival and inflammation. The consequent sustained release of pro‐inflammatory cytokines and MMPs promote angiogenesis. Besides, extracellular S100A4 interacted with RAGE exerts an inhibitory effect on autophagy through activating β‐catenin signalling pathway. On the other hand, extracellular S100A4 activates TLR4/ERK1/2 pathway to abrogate caspase‐9‐dependent apoptosis. Meanwhile, extracellular S100A4 induces inflammatory response partly mediated by TLR4 and through the activation of NF‐κB axis, the kinases p38 and ERK1/2. In addition, extracellular S100A4 increases the expression of α‐SMA through activating of c‐Myb and S1P pathway. Extracellular S100A4 also can affect T cell differentiation by the alteration of T cell polarization balance toward the Th2 phenotype. RAGE, receptor for advanced glycosylation end products; TLR4, Toll‐like receptor 4; MMPs, matrix metalloproteinases; ERK1/2, extracellular signal‐regulated kinase; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells；S1P, sphingosine‐1‐phosphate; α‐SMA, α‐smooth muscle actin
Figure 2
Figure 2
Targeting S100A4 protein function as potential therapies. S100A4 protein that has been released into the extracellular space exerts a vast array of activities, which presents a broad range of potential therapeutic strategies, including the inhibition of S100A4 protein expression, the prevention of S100A4 protein secretion and blocking S1004 protein‐receptor interactions. The expression and secretion of S100A4 can be effective reduced by the use of specific short hairpin RNA (shRNA) molecules and S100A4‐specific siRNA. Besides, LY294002 treatment can decrease S100A4 expression and secretion through inhibiting PI3K/Akt pathway. In addition, paclitaxel can reduce S100A4 expression by decreasing S100A4 nuclear import. Calcimycin, niclosamide and sulindac can mediate S100A4 expression through reducing S100A4 transcription. Pattern recognition receptors can also directly be targeted. TLR4 can be blocked by the CRX‐526, a synthetic lipid A mimetic molecule, and a small molecule inhibitor TAK‐242 (also called resatorvid). RAGE can be blocked by the small‐molecule inhibitor TTP488. In addition, S100A4 can be blocked by S100A4‐neutralizing antibodies. RAGE, receptor for advanced glycosylation end products; TLR4, Toll‐like receptor 4
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