A comprehensive update on the ligands and functions of Mincle Mincle was first identified in 1999 as an NF-IL6-dependent C-type lectin induced in macrophages by lipopolysaccharides; but no ligands were identified for a long time. In their Review, Xiuyuan Lu, Masahiro Nagata and Sho Yamasaki (p. 233) outline the subsequent characterization of Mincle and its importance in a wide range of responses to pathogens and to host cell damage. The authors detail the many ligands that have now been discovered, which enable protection from infection and maintain homeostasis. Ligands include exogenous, endogenous and synthetic molecules, for example in mycobacteria, fungi and parasites, and in mammalian cholesterol derivatives and glucosylceramide. The authors describe the signaling molecules downstream of Mincle and discuss how Mincle recognizes its ligands, which are mostly lipid-based, and how its expression is regulated—as well as macrophages, it is expressed in dendritic cells, neutrophils, B cells and even T cells. Finally, the authors discuss the in vivo relevance of Mincle in innate and adaptive immune responses and the therapeutic implications. View largeDownload slide View largeDownload slide Mesenchymal stem cells support antibody production by plasma cells Bone marrow mesenchymal stem cells (BM MSCs) can inhibit functions of T and B cells but can also form niches in which blood cells are maintained. Although several cell types including BM MSCs and molecules including IL-6 are known to support the BM niches in which long-lived plasma cells (PCs) can also produce antibodies, the exact mechanisms remain unclear. Using flow cytometry to isolate PDGFRα+Sca-1+ BM MSCs and CD138+ PCs, Kayaba et al. (p. 241) show that, in vitro, the MSCs efficiently support survival of PCs and also enhance antibody (IgG and IgM) production. IL-6 is important but other potential factors are identified. In vitro, contact between MSCs and PCs is needed for optimal enhancement of antibody production; in vivo, a minor population of PCs co-localize with PDGFRα+Sca-1+ MSCs. Single-cell RNA sequencing shows that the MSCs are a heterogeneous population and four different types can be identified (PC1–PC4). The authors discuss how these might have different functions in supporting the survival and functions of PCs. View largeDownload slide View largeDownload slide Delineation of the pathway for BATF2-mediated up-regulation of DUSP2 Initially identified as inhibitors of AP-1, the BATF family of transcription factors has many novel roles; for example, BATF2 regulates TLR7-induced IL-12 p40 production in macrophages, and BATF2 deficiency attenuates the anti-tumor effects of TLR7. DUSP2 is a phosphatase expressed only in immune cells and attenuates phospho-STAT3; like Batf2–/– macrophages, Dusp2–/– macrophages have impaired TLR-induced responses, including IL-12 p40 production. Comparing Batf2–/– and wild-type (WT) macrophages, Kanemaru et al. (p. 255) show that Dusp2 histone acetylation (associated with transcription) and DUSP2 expression are lower in vitro and in vivo in response to TLR7 ligands. In TLR7-stimulated Batf2–/– macrophages, phospho-STAT3 and IκB are up-regulated but NF-κB (p50 and p65) and IL-12 p40 levels are down-regulated compared with WT; the proportion of Th1 cells is also reduced. The authors identify the recruitment sites for BATF2 in the Dusp2 promotor and thus show that NF-κB p65 binds BATF2 there to enhance DUSP2 expression and, via phospho-STAT3 dephosphorylation, regulates IL-12 p40 production. View largeDownload slide View largeDownload slide Macrophage responses depend on the stiffness of the surface to which they attach Macrophages function in tissues that differ considerably in physical characteristics such as stiffness. In vitro, different stiffnesses can be modeled by polyacrylamide growth substrates coated onto glass. The consequent ‘mechanotransduction’ effects on macrophages are little studied; however, the kinases ROCK1/2 are known to regulate the cytoskeleton downstream of integrin attachment to extracellular matrix. Here, Gruber et al. (p. 267) examine Toll-like receptor (TLR)-mediated responses of macrophages cultured on fibronectin-coated glass or on fibronectin-coated polyacrylamide gels of varying stiffness. Unstimulated or TLR9-stimulated bone marrow-derived macrophages (BMMs) have different shapes on surfaces with differing, but physiologically relevant, stiffness. TLR4- or TLR9-mediated TNFα release from BMMs or the RAW264.7 macrophage cell line also depends on substrate stiffness. Inhibition of ROCK1/2 in macrophages enhances phosphorylation of signaling molecules downstream of TLR4 (p38, ERK1/2 and NFκB). The authors thus characterize a novel signaling pathway whereby the physical mechanics of the environment regulate macrophage functions. View largeDownload slide View largeDownload slide Published by Oxford University Press on behalf of The Japanese Society for Immunology 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.
International Immunology – Oxford University Press
Published: May 24, 2018
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