Journal de biologie des cytokines

Abstrait

GMEssential Role of GM-CSF-Dependent Macrophages in Human Autoimmune and Inflammatory Responses

Rui Yamaguchi, Arisa Sakamoto, Reona Yamaguchi, Misa Haraguchi, Shinji Narahara, Hiroyuki Sugiuchi and Yasuo Yamaguchi

Macrophages are important cells in the innate immune system that express toll-like receptors, produce various cytokines, and have a major role in both inflammation and autoimmune diseases. These cells undergo differentiation into GM-CSF-dependent or M-CSF-dependent macrophages in response to influences in the microenvironment. Because there are marked physiological and immunological differences between mice and humans, the inflammatory response of human macrophages is not accurately reproduced by murine models. GM-CSF and M-CSF are factors that promote the differentiation of bone marrow progenitor cells and induce various changes of human macrophage lineages. GM-CSF also promotes activation of pathways involved in immunity by upregulating the expression of various receptors. While cross-talk among these receptor-mediated signaling pathways is complicated, it is known that binding of different receptor ligands results in quantitative/qualitative changes of cytokine production. GM-CSFdependent macrophages produce pro-inflammatory cytokines that are known as type 1 T helper cell (Th1) cytokines. Among them, IL-23 is a pro-inflammatory cytokine required for differentiation of Th17 cells, which are involved in autoimmunity and inflammation. Pathogenic IL-23 signaling is considered to initiate autoimmune processes that are driven by GM-CSF-dependent macrophages. This review focuses on the complex intracellular signaling pathways activated in GM-CSF-dependent human macrophages by several receptors. A model is proposed, in which crosstalk among multiple signal transduction pathways leads to reactivation of autoimmune and inflammatory responses.