Toll-like receptor-mediated, enhanced production of profibrotic TIMP-1 in monocytes from patients with systemic sclerosis: role of serum factors

Ciechomska, Marzena; Huigens, Christiaan; Hügle, Thomas; Stanly, Tess A.; Geßner, Andreas; Griffiths, Bridget; Radstake, Timothy R D J; Hambleton, Sophie; O’Reilly, Steven; Laar, Jacob M van

doi:10.1136/annrheumdis-2012-201958

Cited by 60 publications

(59 citation statements)

References 36 publications

(35 reference statements)

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“…HC monocytes were pre-treated with human immunoglobulin G (IgG) for 1 h prior to HC or SSc sera stimulation (IgG block) and HC or SSc sera were incubated with RNA/DNA endonuclease (benzonase) prior to sera stimulation or interleukin-1 receptors-associated kinase 4 (IRAK4 − /− ) monocytes were treated with HC and SSc sera and tissue-inhibitor of metalloproteinase-1(TIMP-1) secretion was measured by ELISA. The data show that RNA and IgG receptors play a role in induction of profibrotic TIMP-1 and that IRAK4 is critical in this process (38). *** Significantly different analysis of variance (ANOVA).…”

Section: Resultsmentioning

confidence: 97%

Role of toll-like receptors in systemic sclerosis

Ciechomska

Cant

Finnigan

et al. 2013

Expert Rev. Mol. Med.

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Accumulative evidence demonstrates the crucial role of evolutionary conserved Toll-like receptors (TLRs) in identifying microbial or viral compounds. TLRs are also able to recognise endogenous molecules which are released upon cell damage or stress and have been shown to play a key role in numerous autoimmune diseases including systemic sclerosis (SSc). A classic feature of SSc, is vascular injury manifested as Raynaud's phenomenon and ischaemia of the skin, resulting in the release of endogenous TLR ligands during inflammation and local tissue damage. These locally released TLR ligands bind TLRs possibly complexed to autoantibodies, and initiate intracellular signalling pathways and may be one of the mechanisms that initiate and drive autoimmunity and subsequent fibrosis. Activation of the immune system results in interferon (IFN) sensitive gene transcription. There is also an IFN gene signature in SSc peripheral blood. TLRs may represent the link between immune activation, common in SSc, and tissue fibrosis. Therefore, a better understanding of the mechanisms of TLR-mediated pathogenesis and therapies targeting individual TLRs, may provide a more specific approach of treating multi-systemic autoimmune diseases. This review aims to integrate the current knowledge of TLR function in the autoimmune disorders with particular emphasis on SSc. We suggest the TLR system as a new therapeutic target.

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Section: Resultsmentioning

confidence: 97%

Role of toll-like receptors in systemic sclerosis

Ciechomska

Cant

Finnigan

et al. 2013

Expert Rev. Mol. Med.

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“…TIMP-1 production has been described in circulating monocytes of SSc compared with RA patients and controls. When SSc and control monocytes were stimulated with TLR8 agonist, TIMP-1 production dramatically elevated, underlining the role of TLR signaling in ECM remodeling [136].…”

Section: Systemic Sclerosismentioning

confidence: 97%

Toll-Like Receptor Pathways in Autoimmune Diseases

Chen

Szodoray

Zeher

2015

Clinic Rev Allerg Immunol

242

177

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Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen.Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location；the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. Particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathways regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. KEYWORDS:Toll-like receptors (TLRs); autoimmune disease; IL-1 receptor associated kinase (IRAK); TNF receptor associated factor (TRAF); Suppressor of cytokine signaling (SOCS) 3 Autoimmune diseases are characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Even though the accurate etiology and pathogenesis of the majority of these diseases are still not clear, complex elements, including genetic, environmental, hormonal factors may provoke the autoimmune processes leading to the development of the disease.Concerning the role of derailed immune responses in the pathogenesis, aberrant processes both in the innate and adaptive immune system have been shown to participate in the disease initiation and perpetuation [1]. Within these processes, numerous studies have been demonstrated that Toll-like receptors (TLRs) have an essential role in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. [2,3]. Toll-like receptorsThe innate immune system is the first line of host defense mechanisms against invading microorganisms and forms the basis of the development of adaptive immunity. Host cells express diverse pattern recognition receptors (PRRs) include toll-like receptors (TLRs), C-type lectin-like receptors (CL...

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“…Agarwal et al demonstrated that SSc fibroblasts upregulated TLR3 in response to interferon-α and that this results in enhanced production of IL-6 and monocyte chemoattractant protein-1 (MCP-1) [14], ultimately leading to enhanced recruitment of monocytes in the tissue. We have previously found that stimulation of TLR8 with single-stranded RNA in monocytes leads to increased TIMP-1 secretion [38] (Fig. 2).…”

Section: Intracellular Tlrsmentioning

confidence: 75%

“…2). Further to this, using a patient with a genetic lesion in IRAK4, we could show that this was both IRAK4 and NF-κB-dependant through incubation of the patient's serum with benzonase, an enzyme that facilitates the cleavage of RNA, which leads to diminished induction of TIMP-1 [38]. It is suggested that the RNA species in the SSc patient's serum is complexed with autoantibodies and that this is stimulating the monocytes to produce TIMP-1.…”

Section: Intracellular Tlrsmentioning

confidence: 95%

Role of innate immune system in systemic sclerosis

Fullard

O’Reilly

2015

Semin Immunopathol

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Recognition of microbial or viral compounds is crucial to elicit an immune response and pattern recognition receptors (PRRs) form the first line of defence. An important family of PRRs are the Toll-like receptors (TLRs) with numerous evidences indicating their crucial role in identifying microbial or viral compounds. However, the danger theory, where the innate immune system responds to danger signals such as proteins released during damage or necrosis rather than only non-self is gaining ground. Indeed, TLRs are able to recognise endogenous molecules and have been implicated as key players in numerous autoimmune diseases including systemic sclerosis (SSc). TLR2 is known to be upregulated in SSc and has been shown to respond to the endogenous ligand amyloid A resulting in increased IL-6 secretion. TLR4 is now known to respond to a variety of endogenous ligands including fibronectin, containing alternatively spliced exons encoding type III repeat extra domain (EDA). EDA is only expressed upon tissue damage, and elevated levels can be found in SSc patients, idiopathic pulmonary fibrosis and cardiac allograft fibrosis, while deletion of EDA or TLR4 in mice reduces their fibrotic response. Further, stimulation of TLR8 with single-stranded RNA leads to increased expression of TIMP-1. This has been shown to require both IRAK4 and NF-κB with evidence suggesting autoantibodies bind to RNA to stimulate TIMP-1 production in monocytes. Therefore, TLR-mediated signalling provides numerous potential therapeutic targets for development of therapies for the treatment of multi-systemic autoimmune diseases.

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Toll-like receptor-mediated, enhanced production of profibrotic TIMP-1 in monocytes from patients with systemic sclerosis: role of serum factors

Cited by 60 publications

References 36 publications

Role of toll-like receptors in systemic sclerosis

Role of toll-like receptors in systemic sclerosis

Toll-Like Receptor Pathways in Autoimmune Diseases

Role of innate immune system in systemic sclerosis

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