The level of synovial AXL expression determines the outcome of inflammatory arthritis, possibly depending on the upstream role of TGF-β1

Waterborg, Claire E J; Broeren, Mathijs G A; Davidson, E.N. Blaney; Koenders, Marije I.; Lent, P.L.E.M. van; Berg, Wim B. van den; Kraan, P.M. van der; Loo, Fons A. J. van de

doi:10.1093/rheumatology/key337

Cited by 19 publications

(23 citation statements)

References 45 publications

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“…Thus, reduced availability of Gas6 would impair the anti-inflammatory function of this molecule due reduced membrane TAM receptor activation. In fact, the protective role of both TAM receptor ligands Gas6 and Pros1 has already been described by our group in murine models of arthritis [ 16 , 17 , 41 ]. In these studies, Gas6 and Pros1 overexpression decreased arthritis severity, by reducing inflammation and by inhibiting the expression of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 91%

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis

Vullings

Vago

Waterborg

et al. 2020

Journal of Immunology Research

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Objective. To investigate the role of TAM receptors in rheumatoid arthritis (RA) by determining synovial tissue TAM receptor expression, synovial fluid levels of soluble TAM receptors, and the relationship between soluble TAM receptors, joint inflammation and disease activity. Methods. TAM receptor expression was determined by immunohistochemistry on the synovium from RA and osteoarthritis (OA) patients. Soluble (s) Tyro3, sAxl, sMer, and their ligand Gas6 were measured by ELISA in the synovial fluid of RA (n=28) and OA (n=12) patients and cytokine levels by multiplex immunoassay in RA samples. Correlation analyses were performed among sTAM receptors with local cytokine levels; systemic disease parameters like erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and anticyclic citrullinated peptide antibodies (ACPA); and disease activity scores (DAS28-ESR) in RA patients. Results. TAM receptors were expressed on different locations in the synovial tissue (lining, sublining, and blood vessels), and a similar expression pattern was observed in RA and OA patients. Synovial fluid sTyro3 and sMer were significantly enhanced in RA compared to OA patients, whereas no significant differences in sAxl and Gas6 levels were found. In RA samples, sTyro3 levels, but not sMer, correlated positively with proinflammatory local cytokines and the systemic factor erythrocyte sedimentation rate. Moreover, stratification analysis showed high sTyro3 levels positively correlated with higher DAS28-ESR and in RF and ACPA double positive RA patients. Conclusion. sTyro3 in the synovial fluid of RA patients correlates with local inflammatory molecules and systemic disease activity. These findings suggest that the reduced negative control of cell activation by TAM receptors due to their shedding in the synovial fluid, mainly sTyro3, favoring joint inflammation in RA patients.

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Section: Discussionmentioning

confidence: 91%

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis

Vullings

Vago

Waterborg

et al. 2020

Journal of Immunology Research

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“…Axl expression is increased in IL-4 and IL-13 polarized M2 macrophages compared to LPS and IFN-γ M1 polarized macrophages in murine bone marrow-derived macrophages (BMDMs) [58]. AXL transcripts levels are higher in M2-like human monocyte-derived macrophages polarized with M-CSF than M1-like polarized with GM-CSF [59]. In human monocyte-derived macrophages, AXL mRNA is induced following treatment with immunosuppressive M2-stimulant dexamethasone [56].…”

Section: Main Textmentioning

confidence: 99%

Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

Myers¹,

Amend²,

2019

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Tumor-associated macrophages are an abundant cell type in the tumor microenvironment. These macrophages serve as a promising target for treatment of cancer due to their roles in promoting cancer progression and simultaneous immunosuppression. The TAM receptors (Tyro3, Axl and MerTK) are promising therapeutic targets on tumor-associated macrophages. The TAM receptors are a family of receptor tyrosine kinases with shared ligands Gas6 and Protein S that skew macrophage polarization towards a pro-tumor M2-like phenotype. In macrophages, the TAM receptors also promote apoptotic cell clearance, a tumor-promoting process called efferocytosis. The TAM receptors bind the “eat-me” signal phosphatidylserine on apoptotic cell membranes using Gas6 and Protein S as bridging ligands. Post-efferocytosis, macrophages are further polarized to a pro-tumor M2-like phenotype and secrete increased levels of immunosuppressive cytokines. Since M2 polarization and efferocytosis are tumor-promoting processes, the TAM receptors on macrophages serve as exciting targets for cancer therapy. Current TAM receptor-directed therapies in preclinical development and clinical trials may have anti-cancer effects though impacting macrophage phenotype and function in addition to the cancer cells.

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“…Further studies from the same group also showed that in a KRN serum transfer model of arthritis, the absence of Axl (Axl -/-) or Mer (Mer -/-) caused more severe disease in comparison with WT [74,75]. Of note, the exacerbated pathology was observed only in ankles of Axl -/mice, whereas no effect was seen in the knees of Axl KO mice [75]. The histological analysis of the synovial tissue enabled a potential interpretation for this clinical outcome.…”

Section: Tam Receptors Implications In Rheumatoid Arthritismentioning

confidence: 91%

“…While ankle synovium was characterised by high expression of Axl and a predominance of anti-inflammatory M2 macrophages, synovial tissue sampled from the knees had scant M2 macrophages and virtually absent Axl. Mer-deficient mice had instead aggravated disease in all the joints assessed [75].…”

Section: Tam Receptors Implications In Rheumatoid Arthritismentioning

confidence: 96%

New Insights into the Role of Tyro3, Axl, and Mer Receptors in Rheumatoid Arthritis

et al. 2020

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Rheumatoid Arthritis (RA) is the most common chronic inflammatory autoimmune disease involving joints. Among several pathogenic mechanisms, the impairment of homeostatic regulators of inflammation seems to be critically important to sustain persistent infiltration and activation of immune and stromal cells within the diseased synovium. Tyrosine kinase receptors Tyro3, Axl, and Mer are members of the TAM family. Upon binding their ligands Growth Arrest-Specific gene 6 (Gas6) and Protein S (ProS1), TAM receptors (TAMs) exert numerous and diverse biologic functions. Activated Axl and Mer, for instance, can negatively regulate the inflammatory cascade and mediate phagocytosis of apoptotic cells, contributing to prevent the development of autoimmunity. Thus, a role for TAMs has been hypothesized in RA. In this review, we will summarise unmet clinical needs in RA, depict the biology of TAMs and TAM ligands, focussing on their ability to regulate the immune system and inflammation cascade, and finally offer an overview of the state-of-the-art literature about the putative role of TAM axis in RA.

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The level of synovial AXL expression determines the outcome of inflammatory arthritis, possibly depending on the upstream role of TGF-β1

Cited by 19 publications

References 45 publications

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis

Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

New Insights into the Role of Tyro3, Axl, and Mer Receptors in Rheumatoid Arthritis

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