GM-CSF: From Growth Factor to Central Mediator of Tissue Inflammation Burkhard Becher, Sonia Tugues, Melanie Greter  Immunity  Volume 45, Issue 5, Pages 963-973 (November 2016) DOI: 10.1016/j.immuni.2016.10.026 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 The CSF Super Family The M-CSFR is a homodimer that can be expressed across most members of the MPS and can be triggered by its canonical ligand M-CSF as well as IL-34. The latter has been shown to be involved in the homeostasis of both Langerhans cells (LCs) and microglia. The GM-CSFR likewise is expressed broadly by most members of the myeloid compartment. The β chain can pair with the GM-CSF-specific α chain or the α chains forming the receptors for IL-3 and IL-5. GM-CSFR engagement leads to activation and cell differentiation and, in some cells (e.g., MCs), to the initiation of a proinflammatory expression signature. The G-CSFR homodimer is expressed primarily on GCs and is important for the mobilization of granulocytic cells from the BM. Abbreviations are as follows: MF, macrophage; Mo, Monocyte; MC, Monocyte-derived cell; DC, dendritic cell; GC, granulocyte. Immunity 2016 45, 963-973DOI: (10.1016/j.immuni.2016.10.026) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 CSFs in Steady-State Myelopoiesis Primitive yolk sac macrophages give rise to microglia in the CNS, a process highly dependent on M-CSFR signaling. Although this is most likely driven by M-CSF, microglia maintenance in the adult depends on the alternative M-CSFR ligand IL-34. Fetal liver monocytes are the precursors for most tissue macrophages, which in the adult are self-maintaining. M-CSF is important for the development and maintenance of most of them. An exception is the lung, where GM-CSF is critical for the development of alveolar macrophages but also regulates cDC1s. In the systemic circulation, M-CSF and G-CSF control the frequency of monocytes and granulocytes, respectively. Abbreviations are as follows: AM, alveolar macrophage; MF, macrophage; Mo, monocyte; MC, monocyte-derived cell; DC, dendritic cell; GC, granulocyte; YS, yolk sac; and FL, fetal liver. Immunity 2016 45, 963-973DOI: (10.1016/j.immuni.2016.10.026) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 GM-CSF in Inflammation and Cancer (A) In inflammatory conditions, various cell types can produce GM-CSF. Activated T cells are a prominent source of GM-CSF, which acts on MCs to drive an inflammatory signature leading to the release of cytokines and reactive oxygen species (ROS), which can directly cause tissue damage and functional deficit. The impact of GM-CSF on activated granulocytes and tissue-resident DCs and macrophages has been proposed. (B) Tumor cells have been engineered to produce GM-CSF to serve as a vaccine (GVAX, T-VEC), which initiates the accumulation of myeloid cells. DCs are thought to process tumor-associated antigens for the activation and expansion of tumor-specific T cells. Immunity 2016 45, 963-973DOI: (10.1016/j.immuni.2016.10.026) Copyright © 2016 Elsevier Inc. Terms and Conditions