Commanding CNS Invasion: GM-CSF

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSFor Csf-2) is a pro-inflammatory mediator implicated in the pathogenesis of various autoimmune diseases. 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.

IFN‐γ promotes transendothelial migration of CD4+ T cells across the blood–brain barrier

“…IFN‐γ also induced the TEM of in vitro ‐activated CD4 + T cells (Th0), Th1 and Th17 cells (Figure 2d), and peripheral natural regulatory CD4 + T cells (Figure 2e), but had no significant effect on the TEM of memory CD4 + T cells (Figure 2e). CD4 + T cells are known to transmigrate through the inter‐endothelial junctions (paracellular) or the endothelial cell body (transcellular) 16 . To investigate whether IFN‐γ affected the route of the TEM, CFSE‐labeled naive CD4 + CD25 − T cells or in vitro‐ activated CD4 + CD25 + T cells were allowed to transmigrate across the endothelial monolayer from the apical to the basal side towards CCL21.…”

“…CD4 + T cells are known to transmigrate through the inter-endothelial junctions (paracellular) or the endothelial cell body (transcellular). 16 To investigate whether IFN-γ affected the route of the TEM, CFSE-labeled naive CD4 + CD25 − T cells or in vitro-activated CD4 + CD25 + T cells were allowed to transmigrate across the endothelial monolayer from the apical to the basal side towards CCL21. The transmigration routes were analyzed using a confocal microscope.…”

“…Total RNA was also purified from the CD31 + CD45 − endothelial cells isolated from brain tissues using flow cytometry sorting. The RNA extract was treated with the DNase I kit (Invitrogen) to remove genomic DNA, and then cDNA was prepared with the RT-PCR kit (Invitrogen) using oligo d(T) [12][13][14][15][16] primers as per the manufacturer's guidelines. Expressions of specific genes were quantified using the SYBR Green PCR kit (Life Technologies) in a CFX96 thermal cycler (Biorad, Hercules, CA, USA).…”

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms

“…It is unknown if reduced lymphocytes in circulation reflect margination or target tissue migration, although probable. Plasma granulocyte macrophage colony-stimulating factor (GM-CSF) levels were significantly higher in CoV-CNS patients , which may drive the expansion of CNS-invading phagocytes (e.g., inflammatory monocyte-derived cells; MdC such as dendritic cells) (Zhao et al, 2017). In fact, GM-CSF has emerged as a potential biological target in treating severe COVID-19 ; this may mitigate neuropsychiatric sequelae by limiting MdC neuroinvasion.…”

Granulocyte-Macrophage Colony-Stimulating Factor as a Therapeutic Target in Multiple Sclerosis

“…GM-CSF can modulate cytokine and chemokine expression by mature myeloid-derived cells and upregulate costimulatory molecules and major histocompatibility complex (MHC) class II molecules[ 70 – 72 , 74 ]. As the expression of GM-CSF restricted to CNS-infiltrating CD4+ T cells alone is sufficient to cause disease [ 65 , 68 ], its essential role may be effector cell differentiation within the CNS, establishing a complex pro-inflammatory feedback system involving APCs, neutrophils, microglia and endothelial cells [ 71 , 75 ].…”