Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System

Abstract

Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits. CNS-invading phagocytes produced reactive oxygen species and exhibited a distinct genetic signature compared to myeloid cells invading other organs. We propose that the CNS is particularly vulnerable to the attack of monocyte-derived phagocytes and that the effector functions of GM-CSF-expanded myeloid cells are in turn guided by the tissue microenvironment.

GM-CSF Quantity Has a Selective Effect on Granulocytic vs. Monocytic Myeloid Development and Function

“…Previous studies showed that GM-CSF overexpression resulted in an increase in both Ly6G + granulocytes and monocytic myeloid cells (14, 29). Nevertheless, we observed that increase in monocytic myeloid cells in GMtg mice was greater than increase in granulocytes in spleen (Figures 1C–G).…”

“…Apart from spleen, there was a greater increase in monocytic myeloid cells in blood (Supplementary Figure 1B), lung (Supplementary Figure 1B) and liver (Supplementary Figure 1C). As Ly6C can be downregulated on monocytes/macrophages under high levels of GM-CSF (14, 29), expression of CCR2 reporter we also used to aid identification of monocytic myeloid cell subsets. When monocytic cells were further separated into CCR2 + (either Ly6C hi and Ly6C lo ) and Ly6C − CCR2 − cells, increase in CCR2 + cells in GMtg mice was more prominent (Supplementary Figures 1A–C).…”

“…In another study where two lines of GMtg mice with different levels of GM-CSF were examined, it was the strain with higher GM-CSF that had the greater increase in spleen monocytes than granulocytes (32). In a recent study with GM-CSF overexpression, increase in monocytic myeloid cells in brain tissue was more prominent (29). Here we compared the two lineages of myeloid cells in WT (representing low levels of endogenous GM-CSF) and GMtg (representing elevated GM-CSF) mice.…”

CNS inflammation and neurodegeneration

“…In EAE, GM-CSF production by Th17 cells activates effector mononuclear phagocytes (89). GM-CSF-activated mononuclear phagocytes that migrate into the CNS exhibit a more pathogenic signature than those that migrate to other organs, which may be due to the unique CNS microenvironment (61).…”

Commanding CNS Invasion: GM-CSF

“…In this issue of Immunity , Spath et al show that the dysregulated production of GM-CSF rather than IL-17 induces spontaneous immunopathology in a mouse model of CNS inflammation. …”