Increased plasma levels of the soluble Mer tyrosine kinase receptor in systemic lupus erythematosus relate to disease activity and nephritis

Abstract

IntroductionMer and Tyro3 are receptor tyrosine kinases important for the phagocytosis of apoptotic cells. Together with Axl, they constitute the TAM receptor family. These receptors can be shed from the cell membrane and their soluble extracellular regions can be found in plasma. The objective of this study was to elucidate whether the plasma levels of soluble Mer (sMer) and Tyro3 (sTyro3) were increased in systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), or critical limb ischemia (CLI).MethodsELISA kits were used to test plasma concentrations in controls and in patients with SLE, RA or CLI.ResultsIncreased levels of, in particular, sMer and, to some extent, sTyro3, were found in patients with SLE or RA, but not in patients with CLI. Patients with SLE demonstrated the highest sMer levels and there was a strong correlation to higher SLE disease activity score (SLEDAI). In contrast, in patients with RA, the sMer levels did not correlate with the disease activity score (DAS). In SLE, sMer levels were particularly high in those with lupus nephritis, patients who also had decreased C1q levels and increased titers of anti-DNA antibodies. After therapy, the plasma concentrations of sMer decreased in parallel to the decrease in SLEDAI score.ConclusionsThe plasma concentrations of sMer and sTyro3 were significantly increased in patients with active SLE and RA, suggesting the TAM receptor shedding was affected by these autoimmune diseases. In particular, sMer was increased in SLE, the plasma levels of sMer reflecting disease activity.

MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

“…In the setting of advanced atherosclerosis, this profound deficit promotes key features of clinically dangerous plaques, including necrosis, imbalance of proresolving versus proinflammatory lipid mediators, fibrous cap thinning, and deficiency of Tregs. The finding that cleavage of a single molecule in the setting of a chronic inflammatory condition could have such robust pathophysiologic effects not only suggests its potential as a therapeutic target but also raises the question of the possible role of MerTK cleavage in other chronic inflammatory conditions previously linked to MerTK and sol-Mer, e.g., systemic lupus erythematosus and Sjögren's syndrome (35)(36)(37)(38). …”

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

“…This process disables MerTK, and the cleavage product, soluble Mer (sol-Mer), may competitively inhibit the interaction of intact MerTK with its ligands (21,22). Plasma solMer is increased in patients with active systemic lupus erythematosus and rheumatoid arthritis (23,24), and cell-surface MerTK is lower in macrophages in ADAM17-rich areas in advanced human atherosclerotic lesions (25). However, causation studies are lacking.…”

Intima-media thickness in secondary anti-phospholipid syndrome patients: Impact of disease activity

“…It may result from disturbed tolerance to self antigens and development of auto-antibodies leading to the formation of immune complexes. These immune deposits in the tissues initiate an inflammatory response by activating the complement cascade and recruiting inflammatory cells [3,4]. The defective clearance of apoptotic cells [5]; increased oxidative stress [6] and gene polymorphism [7] are believed to be among the multiple causes of SLE.…”