Macrophage-Derived Immunoglobulin M Inhibits Inflammatory Responses via Modulating Endoplasmic Reticulum Stress.

Xiaoting Gong,Zhu Zhu,Shenghua Zhang,Weiyan Xu,Junfan Ma,Jing Huang,Xiaoyan Qiu,Huige Yan

doi:10.3390/cells10112812

Xiaoting Gong, Zhu Zhu + Show 6 more

Open Access

https://doi.org/10.3390/cells10112812

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Abstract

Immunoglobulin (Ig), a characteristic marker of B cells, is a multifunctional evolutionary conserved antibody critical for maintaining tissue homeostasis and developing fully protective humoral responses to pathogens. Increasing evidence revealed that Ig is widely expressed in non-immune cells; moreover, Ig produced by different lineages cells plays different biological roles. Recently, it has been reported that monocytes or macrophages also express Ig. However, its function remains unclear. In this study, we further identified that Ig, especially Ig mu heavy chain (IgM), was mainly expressed in mice macrophages. We also analyzed the IgM repertoire characteristic in macrophages and found that the VHDJH rearrangements of macrophage-derived IgM showed a restricted and conservative VHDJH pattern, which differed from the diverse VHDJH rearrangement pattern of the B cell-expressed IgM in an individual. Functional investigation showed that IgM knockdown significantly promoted macrophage migration and FAK/Src-Akt axis activation. Furthermore, some inflammatory cytokines such as MCP1 and IL-6 increased after IgM knockdown under LPS stimulation. A mechanism study revealed that the IgM interacted with binding immunoglobulin protein (Bip) and inhibited inflammatory response and unfolded protein response (UPR) activation in macrophages. Our data elucidate a previously unknown function of IgM in macrophages that explains its ability to act as a novel regulator of Bip to participate in endoplasmic reticulum stress and further regulate the inflammatory response.

Highlights

It is well known that immunoglobulin M (IgM) is an ancient molecule that is the first antibody isotype to appear as a specific product of the B cell lineage during evolution [1,2]
Recent evidence revealed that Ig mu heavy chain (IgM) and IgG were expressed in human CD14+ monocytes and macrophages induced by IFN-γ, as well as CD11b+ bone marrow macrophages of C57BL/6 mice [16,18]
We further identified if different classes of Ig heavy chain and light chain, such as IgG, IgM, IgA, Igκ, or Igλ can be expressed in these macrophages

Summary

Introduction

It is well known that immunoglobulin M (IgM) is an ancient molecule that is the first antibody isotype to appear as a specific product of the B cell lineage during evolution [1,2]. IgM is divided into both membrane and secretory. The membrane IgM appears as a monomer, which is only located on the B cell membrane and responsible for recognizing antigens and activating B cells. The function of secretory IgM has long been determined only to exert antibody activity, which can be divided into natural IgM and immune IgM [3]. Natural IgM, which shows poly-reactivity and low-affinity, can be spontaneously secreted in an antigen-independent manner to recognize multiple epitopes of different microbial common antigens and exert natural antibody activity. Immune IgM can recognize only one epitope under antigen stimulation and exert adaptor humoral immune function [3]

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