GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease

Abstract

Experimental autoimmune encephalomyelitis (EAE) has been used as an animal model of multiple sclerosis to identify pathogenic cytokines that could be therapeutic targets. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is the only cytokine reported to be essential for EAE. We investigated the role of GM-CSF in EAE in C3HeB/FeJ mice that uniquely exhibit extensive brain and spinal cord inflammation. Unexpectedly, GM-CSF-deficient C3HeB/FeJ mice were fully susceptible to EAE because IL-17 activity compensated for the loss of GM-CSF during induction of spinal cord-targeted disease. In contrast, both GM-CSF and IL-17 were needed to fully overcome the inhibitory influence of IFN-γ on the induction of inflammation in the brain. Both GM-CSF and IL-17 independently promoted neutrophil accumulation in the brain, which was essential for brain-targeted disease. These results identify a GM-CSF/IL-17/IFN-γ axis that regulates inflammation in the central nervous system and suggest that a combination of cytokine-neutralizing therapies may be needed to dampen central nervous system autoimmunity.

Pathogenic T cell cytokines in multiple sclerosis

“…Effector T cell priming is compromised in the absence of GM-CSF (McQualter et al, 2001;Sonderegger et al, 2008;King et al, 2009;Pierson and Goverman, 2017;Duncker et al, 2018), which may contribute to the complete resistance of mice deficient in GM-CSF and its receptor in some strains. GM-CSF receptors are not expressed on T cells (Morrissey et al, 1987), suggesting that the effects of GM-CSF on T cell priming is indirect.…”

Deficiency of Socs3 leads to brain-targeted experimental autoimmune encephalomyelitis via enhanced neutrophil activation and ROS production

“…We and others have demonstrated that brain-targeted, atypical EAE is predominantly a neutrophil-driven disease (11,13,44,48,49,73,74). Previously, we reported that neutrophils increase production of proinflammatory cytokines, chemokines, and nitric oxide during onset of atypical EAE in Socs3 ΔLysM mice (44).…”

“…To exclude the possibility that treatment with the ROS scavenger cocktail suppresses atypical EAE by affecting T cell priming, we determined the frequency of myelin oligodendrocyte glycoprotein-specific (MOG-specific) T cells after treatment. The frequency of MOG-specific T cells, determined by cytokine production upon either MOG stimulation (Supplemental Figure 2A) or MOG [38][39][40][41][42][43][44][45][46][47][48][49] tetramer staining (Supplemental Figure 2, C and D), were comparable between ROS scavenger treatment and vehicle control. The percentage of regulatory T cells after ROS scavenger treatment was also not changed (Supplemental Figure 2B).…”

“…Neutrophils have been implicated in both spinal cord-targeted, classical EAE (19,20,46,47) as well as brain-targeted, atypical EAE (44,(48)(49)(50), although there is controversy about their exact functions. To address the role of neutrophils in atypical EAE, we first determined levels of surface receptors on cerebellar-infiltrating neutrophils using multicolor flow cytometry analysis (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.126520DS1).…”

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

“…Likewise, neutralizing IFNγ exacerbated disease and made an EAE-resistant mouse strain susceptible (40, 41, 43-46). These studies were corroborated by eliminating IFNγ signaling using genetic deletion of Ifng or Ifngr1 , which resulted in higher susceptibly to EAE, increased incidence, more extensive inflammation, encompassing both the spinal cord and hindbrain, and exacerbated disease compared to WT animals (47-55). Further, only mice with intact IFNγ signaling were able to recover from EAE (56).…”