Mannose-Binding Lectin Blunts Macrophage Polarization and Ameliorates Lupus Nephritis

Abstract

BackgroundDeficiency in clearance of self nuclear antigens, including DNA, is the hallmark of systemic lupus erythematosus (SLE), a chronic autoimmnue disease characterized by the production of various autoantibodies, immune complex deposition and severe organ damage. Our previous studies revealed that administration of syngeneic BALB/c mice with activated lymphocyte-derived DNA (ALD-DNA) could induce SLE disease. Mannose-binding lectin (MBL), a secreted pattern recognition receptor with binding activity to DNA, has been proved to be a modulator of inflammation, but whether MBL takes responsibility for DNA clearance, modulates the DNA-mediated immune responses, and is involved in the development of DNA-induced SLE disease remain poorly understood.Methodology/Principal FindingsThe levels of serum MBL significantly decreased in lupus mice induced by ALD-DNA and were negatively correlated with SLE disease. MBL blunted macrophage M2b polarization by inhibiting the MAPK and NF-κB signaling while enhancing the activation of CREB. Furthermore, MBL suppressed the ability of ALD-DNA–stimulated macrophages to polarize T cells toward Th1 cells and Th17 cells. Importantly, MBL supplement in vivo could ameliorate lupus nephritis.Conclusion/SignificanceThese results suggest MBL supplement could alleviate SLE disease and might imply a potential therapeutic strategy for DNA-induced SLE, which would further our understanding of the protective role of MBL in SLE disease.

Mannan‐binding lectin attenuates acetaminophen‐induced hepatotoxicity by regulating CYP2E1 expression via ROS‐dependent JNK/SP1 pathway

“…In the present study, we investigated the signaling pathway and found that the phosphorylations of JNK, ERK and p38 were all significantly increased in MBL –/– mice after APAP treatment, suggesting that MBL attenuates the hepatic activation of MAPKs pathway in the context of APAP overdosing. The result is consistent with our and others’ previous reports showing that MBL could significantly down‐regulate the phosphorylation of MAPKs in different cell types in response to various stimulation . Among the MAPKs, JNK acts as a central player in the pathophysiology of APAP‐induced liver injury .…”

M2b macrophage polarization and its roles in diseases

“…IL‐6 is highly expressed in M1 and M2b macrophages but not in M2a and M2c . Growing data show that in combination with other markers (IL‐10, LIGHT, CCL1, or/and TNF‐α), IL‐6 can identify M2b from the other macrophage subsets …”

“…In lupus nephritis (LN), activated lymphocyte‐derived DNA (ALD‐DNA) induces the macrophage activation and M2b polarization by activating the NF‐κB and the IRF3 signaling pathways via calcium signaling . Moreover, the activation of NF‐κB as well as MAPK signaling in macrophages is inhibited by mannose‐binding lectin (MBL), a recognition receptor with binding activity to DNA, resulting in a decrease in M2b macrophage polarization . Furthermore, ALD‐DNA‐induced M2b polarization is dependent on the acceleration of NF‐κB p50 translocation into the nucleus mediated by the PI3K and MAPK pathways .…”

“…After dectin‐1 binding to zymosan (a component derived from fungi), kinases ERK1/2 and p38 are activated and induce M2b macrophage polarization by provoking mitogen‐ and stress‐activated protein kinase‐1/2 (MSK1/2) . Moreover, MBL blunts macrophage M2b polarization by inhibiting MAPK and NF‐κB signaling . These observations suggest that the MAPK signal is a crucial positive modulator of M2b macrophage polarization.…”

“…71,78 Growing data show that in combination with other markers (IL-10, LIGHT, CCL1, or/and TNF-), IL-6 can identify M2b from the other macrophage subsets. 30,71,[77][78][79][80][88][89][90] In addition to the above molecules, other molecules used to identify M2b macrophages include MHCII/HLA-DR, CD163, CD64, PD-L1 IL-1 , and CCL2. 26,27,30,75,[91][92][93] However, these molecules are not specific markers of M2b, nor even specific markers of macrophages.…”