The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease

Abstract

Already 20 years have passed since the cloning of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor ␣-chain, the first member of the GM-CSF/ interleukin (IL)-3/IL-5 family of hemopoietic cytokine receptors to be molecularly characterized. The intervening 2 decades have uncovered a plethora of biologic functions transduced by the GM-CSF receptor (pleiotropy) and revealed distinct signaling networks that couple the receptor to biologic outcomes. Unlike other hemopoietin receptors, the GM-CSF receptor has a significant nonredundant role in myeloid hematologic malignancies, macrophage-mediated acute and chronic inflammation, pulmonary homeostasis, and allergic disease. The molecular mechanisms underlying GM-CSF receptor activation have recently been revealed by the crystal structure of the GM-CSF receptor complexed to GM-CSF, which shows an unexpected higher order assembly. Emerging evidence also suggests the existence of intracellular signosomes that are recruited in a concentration-dependent fashion to selectively control cell survival, proliferation, and differentiation by GM-CSF. These findings begin to unravel the mystery of cytokine receptor pleiotropy and are likely to also apply to the related IL IntroductionGranulocyte-macrophage colony-stimulating factor (GM-CSF) and the related cytokines interleukin (IL)-3 and IL-5 regulate the production and functional activation of hemopoietic cells, with GM-CSF acting on monocyte/macrophages and all granulocytes. 1 GM-CSF also controls dendritic cell and T-cell function, 2 thus linking innate and acquired immunity. Because of the widespread expression of the GM-CSF receptor in hematopoietic cells, it was assumed that both GM-CSF and its receptor were key players in the regulation of steady-state functions. Whereas this turned out to be true in terms of lung physiology, 3-7 deletion of either the GM-CSF gene or its receptor showed no obvious deficiency in myeloid cell numbers or production. 4,8,9 Rather, a growing body of evidence now suggests that GM-CSF plays a key role in signaling emergency hemopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult. [10][11][12][13] The role of GM-CSF and its receptor in pathology, on the other hand, arises largely as a result of abnormal signaling leading to deregulated myelopoiesis with enhanced proliferation and survival of myeloid precursors, a common feature of myeloproliferative disorders and myeloid leukemias. For example, juvenile myelomonocytic leukemia (JMML), a rare, but potentially fatal myeloproliferative disorder of children clinically presenting with monocytosis, thrombocytopenia, and malignant infiltration of nonhematologic organs by clonal macrophages, 14 exhibits hypersensitivity to 15,16 and a mouse model of JMML shows an absolute requirement for GM-CSF and its receptor in establishment and maintenance of the disease. 17,18...

Nontransformed, GM-CSF–dependent macrophage lines are a unique model to study tissue macrophage functions

“…GM-CSF triggers several signaling pathways and transcription factors such as c-Myc, pim-1, CCAAT/enhancer-binding protein alpha, PU.1, and STAT5 (6,21). Our finding that the expression of caSTAT5 abolished the need for GM-CSF indicates a pivotal role for STAT5 in the proliferation and maintenance of the characteristic proinflammatory phenotype of MPI cells.…”

“…S1A). GM-CSF signaling leads to the induction of several pathways in- cluding the activation of STAT5 (6,21). We found that proliferating MPI cells express activated STAT5, as evidenced by its nuclear localization (Fig.…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…GM-CSF is produced by many types of cells when stimulated with microbial products or inflammatory cytokines and is also produced by antigen-stimulated T lymphocytes (13). GM-CSF stimulates the proliferation and differentiation of committed progenitors that generate neutrophils, monocytes, macrophages and dendritic cells and also activates differentiated myeloid effector cells such as neutrophils, eosinophils, or monocytes to increase their activity or maturation or prolong their survival (14)(15)(16)(17). Small amounts of GM-CSF produced in the lung are necessary for the maturation of alveolar macrophages, which normally catabolize surplus surfactant in the alveoli.…”

Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma

“…GM-CSF plays a critical role in DC maturation and T-cell proliferation and activation, and increases DC-mediated responses to tumor cells. 70 When used as an adjuvant, it might, however, increase MDSCs in the tumor micro-environment and in blood. This deleterious effect remains, however, controversial and its clinical relevance is doubtful.…”