Macrophage Differentiation and Polarization via Phosphatidylinositol 3-Kinase/Akt–ERK Signaling Pathway Conferred by Serum Amyloid P Component

Abstract

Macrophage differentiation and polarization is influenced by, and act on, many processes associated with autoimmunity. However, the molecular mechanisms underlying macrophage polarization in systemic lupus erythematosus (SLE) remain largely debated. We previously demonstrated that macrophage M2b polarization conferred by activated lymphocyte-derived (ALD)-DNA immunization could initiate and propagate murine lupus nephritis. Serum amyloid P component (SAP), a conserved acute-phase protein in mice, has been reported to bind to DNA and modulate immune responses. In this study, murine SAP was shown to promote macrophage-mediated ALD-DNA uptake through binding to ALD-DNA (SAP/ALD-DNA). Moreover, macrophage phenotypic switch from a proinflammatory M2b phenotype induced by ALD-DNA alone to an anti-inflammatory M2a phenotype stimulated with SAP/ALD-DNA were found because of PI3K/Akt–ERK signaling activation. Both in vivo SAP supplements and adoptive transfer of ex vivo programmed M2a macrophages induced by SAP/ALD-DNA into SLE mice could efficiently alleviate lupus nephritis. Importantly, increased IL-10 secretion, accompanied by anti-inflammatory effect exerted by M2a macrophages, was found to predominantly impede macrophage M2b polarization. Furthermore, neutralization of IL-10 notably reduced the suppressive effect of M2a macrophages. Our results demonstrate that binding of SAP to ALD-DNA could switch macrophage phenotypic polarization from proinflammatory M2b to anti-inflammatory M2a via PI3K/Akt–ERK signaling activation, thus exerting protective and therapeutic interventions on murine lupus nephritis. These data provide a possible molecular mechanism responsible for modulation of macrophage polarization in the context of lupus nephritis and open a new potential therapeutic avenue for SLE.

Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

“…The gene networks generated from M2/2.WT cells indicated ERK 1/2 as the main regulatory hub (P value 5 10 240 , 34 molecules), whereas the top predicted network generated from cells lacking pTyr-721 was centered on NF-kB (P value 5 10 236 , 30 molecules; supplemental Table 4), both of which have been linked to regulation of inflammation [48][49][50][51][52] and macrophage polarization. [51][52][53] Additional data mining on gene expression signatures previously associated with the CSF-1-mediated macrophage shift toward an M2 phenotype in Table 1) that encode secreted cytokines, illustrating the pTyr-721-mediated change in abundance of transcripts encoding M1 (*) and M2 (**) molecules (P , .05, FC . 1.5).…”

“…The gene networks generated from M2/2.WT cells indicated ERK 1/2 as the main regulatory hub (P value 5 10 240 , 34 molecules), whereas the top predicted network generated from cells lacking pTyr-721 was centered on NF-kB (P value 5 10 236 , 30 molecules; supplemental Table 4), both of which have been linked to regulation of inflammation [48][49][50][51][52] and macrophage polarization. [51][52][53] Additional data mining on gene expression signatures previously associated with the CSF-1-mediated macrophage shift toward an M2 phenotype in 54,55 identified a significant overlap in gene identity and direction of regulation between the 96 genes differentially expressed in M1 vs M2 polarized macrophages 54 and 19 of our pTyr-721-regulated transcripts (supplemental Figure 2D). Consistent with the increased lipid metabolism and glycolysis in M1 polarized macrophages, 55 we observed a significant enrichment in cholesterol synthesis-, glycolysis-, and gluconeogenesisrelated genes in pTyr-721-deficient macrophages (supplemental Figure 2E).…”

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

“…1 Moreover, pathology is frequently associated with dynamic changes of macrophage polarization, with M1 macrophages implicated in initiating and sustaining acute inflammation and M2 macrophages associated with resolution or smoldering chronic inflammation. [9][10][11][12] Thus, macrophage polarization is an important component of many disease states, including infection, insulin resistance, atherosclerosis, cancer, and autoimmune disease. 3,[13][14][15] The identification of molecular mechanisms underlying macrophage plasticity and polarization provides a basis for macrophage-centered diagnostic and therapeutic strategies.…”

DNA-dependent Activator of Interferon-regulatory Factors (DAI) Promotes Lupus Nephritis by Activating the Calcium Pathway

“…Data are representative of results obtained in three independent experiments. and in vivo (25,26). To ascertain the role of DAI in ALD-DNAinduced macrophage activation, we examined the expression of activation markers in siDAI-treated macrophages.…”

“…Further study demonstrated that ALD-DNA immunization led to macrophage infiltration and aberrant activation and M2b polarization in murine renal tissues, which mediated the onset and aggravation of SLE disease (25,26), suggesting that ALD-DNA-induced aberrant activation and M2b polarization of macrophage plays a crucial pathogenic role in ALD-DNA-mediated lupus nephritis and autoimmune response.…”