Modulation of TLR2/1 by PAM3CSK4 to induce generation of immunosuppressive macrophages as a therapeutic approach for SLE

Abstract

Abstract Systematic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the overproduction of autoantibodies and the chronic inflammation of multiple organs. Early studies suggested that T and/or B cell abnormalities were critical to disease pathogenesis in lupus patients. More recent work shows that abnormalities in the innate immunity play a contributory if not central role. In that context, we find that SLE patients have significantly more CD14lowCD16+ monocytes compared to healthy controls.CD14lowCD16+ monocytes are a subset known as non-classical monocytes and display inflammatory characteristics upon activation. The frequency of inflammatory macrophages correlates with disease severity and is associated with reduced clearance of apoptotic cells and the overproduction of inflammatory cytokines. We previously found that the TLR2/1 agonist PAM3CSK4 (PAM3) can inhibit the generation of M1- while promoting the generation of immunosuppressive M2-like macrophages. This work examines whether PAM3 can shift the M1:M2 macrophage ratio to restore balance in lupus patients. Even though phenotypically, PAM3 did not seem to induce as many as CD163+ (a functional marker of M2) macrophages like M-CSF did, there was no significant difference in the endocytosis ability of the CD163+ macrophages induced by PAM3 compared M-CSF induced ones. The in vivo activity of PAM3 was investigated in the NZB/W murine model of lupus. Preliminary results indicate that, PAM3 injection increases the survival and decreases proteinuria in mice sera. These findings suggest that PAM3 may promote the polarization of SLE monocytes into immunosuppressive macrophages and thus could represent a novel approach to the therapy of this autoimmune disease.