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

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 V(H)DJ(H) rearrangements of macrophage-derived IgM showed a restricted and conservative V(H)DJ(H) pattern, which differed from the diverse V(H)DJ(H) 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.

Automated summary

The study revealed that Ig, especially Ig mu heavy chain, is mainly expressed in mouse macrophages with a distinct V(H)DJ(H) rearrangement pattern compared to B cell-expressed IgM. Knockdown of IgM in macrophages promoted migration, increased inflammatory cytokines, and activated FAK/Src-Akt axis. IgM was found to interact with Bip to inhibit inflammatory response and UPR activation in macrophages, serving as a novel regulator in endoplasmic reticulum stress and the inflammatory response.