Patients with systemic lupus erythematosus(SLE)are found to be accompanied with innate immunity dysregulation including abnormally macrophage activation.But the functional polarization of the activated macrophages and its underlying molecular mechanism during the pathogenesis of SLE remains unknown.In our study,in the SLE murine model generated by immunization with activated lymphocyte-derived DNA(ALD-DNA),infiltrated macrophages in the nephritic tissues were found to exhibit activation and M2b functional polarization.Notch1 signaling activity was significantly upregulated in the ALD-DNA–induced M2b macrophages in vitro and in vivo.Furthermore,ALD-DNA–induced M2b polarization was found to be dependent on enhanced Notch1 signaling through accelerating NF-kB p50 translocation into the nucleus mediated by PI3K and MAPK pathways.Serum amyloid P component(SAP),a conserved acute-phase protein in mice,has been reported to bind to DNA and modulate immune responses.We found that murine SAP was shown to promote macrophage mediated ALD-DNA uptake through binding to ALD-DNA(SAP/ALD-DNA).SAP/ALD-DNA could switched macrophage from a proinflammatory M2b phenotype induced by ALD-DNA alone to an anti-inflammatory M2a phenotype,which was found because of PI3K/Akt–ERK signaling activation.A plasmid(pSAP)containing SAP coding genes was intramuscularly injected into BALB/c mice in the early stage of SLE disease with the onset of proteinuria reversed lupus nephritis via decreasing anti-dsDNA autoantibody production and immune complex(IC)deposition.Administration of pSAP in the late stage of SLE disease that had established lupus nephritis alleviated proteinuria and ameliorated lupus nephritis.Further study in our lab showed that two cytoplasmic DNA sensors including absent in melanoma 2(AIM2)and DNA-dependent activator of interferon-regulatory factors(DAI)were involved in ALD-DNA-induced macrophage activation and M2b polarization,which might act as important DNA sensors and potential biomarkers for pathological macrophage functional maturation and SLE disease.