Gas6/TAM Receptors in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease associated with impaired immune system regulation. The exact mechanisms of SLE development remain to be elucidated. TAM receptor tyrosine kinases (RTKs) are important for apoptotic cell clearance, immune homeostasis, and resolution of immune responses. TAM deficiency leads to lupus-like autoimmune diseases. Activation of TAM receptors leads to proteolytic cleavage of the receptors, generating soluble forms of TAM. Circulating TAM receptors have an immunoregulatory function and may also serve as biomarkers for disease prognosis. Here, we review the biological function and signaling of TAM RTKs in the development and pathogenesis of lupus and lupus nephritis. Targeting Gas6/TAM pathways may be of therapeutic benefit. A discussion of potential TAM activation and inhibition in the treatment of lupus and lupus nephritis is included.

Figure 1

Pathogenic and therapeutic roles of TAM receptors in lupus. (a) Normal TAM functions in lupus are shown in light blue arrows [–8]. Ligand engagement leads to receptor dimerization and autophosphorylation, which result in the activation of TAM downstream signaling. The effector phase of TAM activation links to apoptotic cell clearance, immune homeostasis, and cell survival/proliferation [8, 21, 35]. TAM activation is reported to be associated with metalloproteinase, ADAM10 and ADAM17, activated cleavage of the receptors [47]. sTAM are released thereby [–51]. (b) Pathogenic roles of TAM receptors are shown in red arrows. Defects of TAM activation occur in several conditions, including inactivation/exhaustion of the ligands, TAM inhibition, and sTAM-mediated inactivation [, –58]. The consequence of impaired TAM function will be the accumulation of apoptotic debris and breakdown of immune tolerance and autoimmune disease develops over time [36, 39]. (c) Potential TAM-targeted therapeutic roles in lupus are shown in the green box [, –79]. Enhancement of TAM activation can be achieved through exogenous administration with TAM ligands, activating Abs, or inhibition of sTAM generation. Construction of constitutive activated TAM is also on the way.