Increased plasma levels of Gas6 and its soluble tyrosine kinase receptors Mer and Axl are associated with immunological activity and severity of lupus nephritis.

Abstract

ObjectiveGrowth arrest-specific 6 (Gas6) and its receptors have been shown to play a crucial role in the homeostasis of the innate immune system by regulating apoptosis and inflammation. We aimed to verify whether an impairment of this system is associated with systemic lupus erythematosus (SLE) disease activity and with lupus nephritis (LN). MerTK (sMer) and Axl (sAxl) concentrations were measured in n=59 SLE patients (n=44 with nephritis, 75%) and analysed in relationship to clinical and laboratory data. Methods Plasma Gas6 and the soluble cleaved form of the receptors ResultsPatients with LN were characterised by higher p=0.03) and sAxl plasma levels than those without ]; p=0.03); conversely sMer plasma concentrations were similar between groups. All the three biomarkers studied were directly correlated to creatinine and daily proteinuria, being inversely related to creatinine clearance. 39 patients had a proteinuria level of <0.5 mg/day, 14 between 0.5 and 3.5 mg/day and 5 had ≥3.5 g/day; Gas6, sAxl and sMer plasma concentrations significantly increased for increasing degree of proteinuria (test for trend p=0.0002; p=0.02; p=0.009, respectively).These correlations were confirmed in multiple linear regression analysis models accounting for gender, age, disease duration and concomitant treatment. Conclusion Plasma Gas6, sAxl and sMer concentrations are associated with the severity of LN in patients affected by SLE.The excess cleavage of TAM receptors might contribute to LN pathogenesis.

Gas6/TAM Axis Involvement in Modulating Inflammation and Fibrosis in COVID-19 Patients

“…To exert its biological activities, Gas6 needs to interact with a specific tyrosine kinase receptor family, collectively named TAM, consisting of three different members, namely Tyro-3, Axl and MerTK, that can be isolated in human plasma as soluble decoy receptors (sTAM: sTyro-3, sAxl, and sMerTK), generated after cleavage of the transmembrane full-length form by membrane matrix metalloproteinases ADAM-10 and ADAM-17. The formation of such Gas6/sTAM complexes represents a useful protection mechanism, intended to limit ligand-mediated signaling and, thus, to prevent the accidental activation of downstream TAM signaling pathways in cells and tissues [ 14 , 15 , 18 , 19 , 20 , 21 ].…”

“…It is noteworthy that Gas6 shows different binding affinities to the different members of the TAM family: it binds with the strongest affinity to Axl (with a Kd in the nM range), and with the lowest affinity to MerTK, with a Kd in the µM range [ 22 , 23 ]. Despite the different binding affinities to TAM receptors, the downstream activation mechanism is similar: once the ligand is bound, the receptor dimerizes and its tyrosine kinase domains become activated, mediating various cellular responses, such as cell growth and proliferation, the regulation of apoptosis, as well as the modulation of vascular and inflammatory responses in a cell and tissue-dependent manner [ 4 , 15 , 18 , 20 , 24 ]. The different cellular responses triggered by the Gas6/TAM axis activation mainly rely on well-known intracellular signaling mediators such as the p38/MAPK, the PI3K/Akt, the ERK1/2 and the JAK/STAT pathways, which need to work in a coordinated manner to ensure homeostasis in the whole organism [ 25 , 26 , 27 ].…”

Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis

“…Interestingly, sIL-6R is cleaved from the membrane by the metalloproteases ADAM10 and 17, both of which are also responsible for Axl cleavage from the cell membrane [ 57 ]. Increased levels of soluble Axl (sAxl) have been associated with the severity of LN [ 58 ]. IL-6 activated STAT3 inhibits microRNA-134a [ 59 ], which is one of the mechanisms responsible for Axl regulation [ 60 ].…”

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters

“…Gas6 biological activities depend on its binding to one of the three members of a family of tyrosine kinase receptors, collectively named TAM (for Tyro-3, Axl, MerTK), which in turn activates different intracellular signaling pathways (i.e., the p38/MAPK, the ERK1/2, the JAK/STAT, and the PI3K/Akt pathways) [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ].…”