Circulating levels of soluble MER in lupus reflect M2c activation of monocytes/macrophages, autoantibody specificities and disease activity

Abstract

IntroductionSystemic lupus erythematosus (SLE) is characterized by impaired efferocytosis and aberrant activation of innate immunity. We asked if shedding of MER receptor tyrosine kinase (MerTK) and AXL into soluble (s) ectodomains was related to immunological and clinical aspects of SLE.MethodsLevels of sMER and sAXL in the plasma of 107 SLE patients and 45 matched controls were measured by ELISA. In 40 consecutive SLE patients, we examined potential correlations between either sMER or sAXL and plasma levels of sCD163, a marker of M2 activation. All three soluble receptors were measured in supernatants of monocytes/macrophages cultured in various immunological conditions. Membrane expression of MerTK, AXL and CD163 was assessed by flow cytometry.ResultsBoth sMER and sAXL were associated with anti-chromatin and anti-phospholipid autoantibodies, and with hematological and renal involvement. However, sMER and sAXL did not significantly correlate with each other; sAXL correlated with growth arrest-specific 6 (Gas6), whereas sMER correlated with reduced free protein S (PROS) levels. Only sMER showed significant associations with lupus-specific anti-dsDNA, anti-Sm, anti-ribonucleoprotein (anti-RNP) and anti-Ro60 autoantibodies. Strong correlations with disease activity indices (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), complement reduction, titer of circulating anti-dsDNA) were found for sMER, not for sAXL. Patients with active SLEDAI, nephritis, anti-dsDNA and anti-Ro60 positivity showed higher levels of sMER compared to controls. Levels of sMER, not sAXL, correlated with sCD163 levels, and these correlated with SLEDAI. Production of sMER and sCD163 occurred under “M2c” polarizing conditions, whereas sAXL was released upon type-I IFN exposure.ConclusionsAlterations in homeostasis of anti-inflammatory and efferocytic “M2c” monocytes/macrophages may have a role in immunopathogenesis of SLE.

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…Recent studies by Zizzo et al [25,69] suggested a strict correlation between systemic lupus erythematosus (SLE) disease severity and the activation of an M2-like macrophage characterized by CD163 and MerTK expression during the monocyte-to-macrophage differentiation. Expanding upon our previous observation that the monocyte compartment becomes perturbed in TB patients [18], we now report that the CD163 + MerTK + pSTAT3 + signature accompanies the expansion of the CD16 + monocytes.…”

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.…”