IL-17A Promotes Granulocyte Infiltration, Myelin Loss, Microglia Activation, and Behavioral Deficits During Cuprizone-Induced Demyelination

Abstract

Recent evidence suggests a pivotal role of the proinflammatory cytokine interleukin - 17A (IL-17) in demyelinating autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS). Nevertheless, it remains unclear if this cytokine exerts direct effects on CNS resident cells during MS or modulates the function of infiltrating immune cells towards a more detrimental phenotype. Here, we investigated the effects of locally produced IL-17 during experimental demyelination of the CNS using the cuprizone (CPZ) model in mice with (GF/IL17) or without transgenic production of IL-17 by astrocytes in the CNS. During early demyelination, GF/IL17 mice demonstrated enhanced activity and decreased anxiety-related behavior in the elevated plus maze suggesting a more severe disease course. Furthermore, in GF/IL17 mice, toxic demyelination was accelerated and synthesis of myelin proteins was reduced. Early demyelination was accompanied by an increased ratio of infiltrating granulocytes in GF/ILl17 mice. The presence of IL-17 during CPZ treatment increased the accumulation of activated microglia and sustained microglial proliferation during myelin loss. Taken together, our results argue for a detrimental role of IL-17 during demyelinating diseases.

Effects of Two Training Programs on Transcriptional Levels of Neurotrophins and Glial Cells Population in Hippocampus of Experimental Multiple Sclerosis

“…The total numbers of microglia in the hippocampus of MS mice was increased during Week 5 after cuprizone treatment. This was in accordance with previous studies showing that after CP treatment, microglia number and activation state increased markedly in mice [14,46,77]. In the present study, HIIT but not LICT, increased numbers of microglia in hippocampus of MS mice.…”

Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression

“…IL‐17 induces neutrophil‐mobilizing/activating factors, including chemokines that target granulocytes, such as CXCL1, CXCL2, and CXCL5 (Iwakura, Ishigame, Saijo, & Nakae, ). Brain‐intrinsic synthesis of IL‐17 has been shown to promote granulocyte infiltration and aggravate myelin loss and behavioral deficits in the cuprizone model (Zimmermann et al, ). This suggests that Th17 lymphocytes infiltrate the forebrain in our Cup/EAE model and recruit granulocytes.…”

Conditional depletion of GSK3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model

“…Loss of myelin was detected by Black Gold staining, which is sensitive to lipid integrity in the GSK3b fl/fl at week 3 of CPZ, whereas, MBP staining or MBP protein analysis did not detect any significant loss in the GSK3b fl/fl at week of CPZ. MBP was shown to be lost at week 3 of CPZ in some studies (Jurevics et al, 2002; Zimmermann et al, ), but not in others (Gudi, Gingele, Skripuletz, & Stangel, ; Matsushima & Morell, 2001). While the discrepancy in demyelination measures may depend on sensitivity of the methods of analysis in our hands, we speculate that this dissociation could reflect a greater vulnerability of the lipid bilayer versus proteins that are embedded in the multilamellar myelin structure.…”