Astrocyte-targeted production of interleukin-6 reduces astroglial and microglial activation in the cuprizone demyelination model: Implications for myelin clearance and oligodendrocyte maturation

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Interleukin (IL)-6 is a pleiotropic cytokine with a potential role in MS. Here we used transgenic mice with astrocyte-targeted production of IL-6 (GFAP-IL6Tg) to study the effect of IL-6 in the cuprizone-induced demyelination paradigm, which is an experimental model of de- and re-myelination, both hallmarks of MS. Our results demonstrated that cuprizone-treated GFAP-IL6Tg mice showed a significant reduction in astroglial and especially microglial activation/accumulation in the corpus callosum in comparison with the corresponding cuprizone-treated wild type (WT). Production of a key microglial attracting chemokine CXCL10, as well as CXCL1 and CCL4 was lower in cuprizone-treated GFAP-IL6Tg mice compared with cuprizone-treated WT. Reduced microglial cell accumulation was associated with inefficient removal of degraded myelin and axonal protection in cuprizone-treated GFAP-IL6Tg mice, compared with WT mice at the peak of demyelination. In addition, transgenic production of IL-6 did not alter initial oligodendrocyte (OL) apoptosis and oligodendrocyte precursor cell recruitment to the lesion site, but it impaired early OL differentiation, possibly due to impaired removal of degraded myelin. Indeed, a microglial receptor involved in myelin phagocytosis, TREM2, as well as the phagolysosomal protein CD68 were lower in cuprizone-treated GFAP-IL6Tg compared with WT mice. Our results show for the first time that astrocyte-targeted production of IL-6 may play a role in modulating experimental demyelination induced by cuprizone. Further understanding of the IL-6-mediated molecular mechanisms involved in the regulation of demyelination is needed, and may have implications for the development of future therapeutic strategies for the treatment of MS. GLIA 2016;64:2104-2119.

Functional antagonism of sphingosine‐1‐phosphate receptor 1 prevents cuprizone‐induced demyelination

“…In the cuprizone demyelination model, Il-6 induced by short-term cuprizone exposure was primarily located to GFAP 1 astrocytes (Tezuka et al, 2013). Using the GFAP-IL-6 transgenic mice, a recent study reported that chronic IL-6 production by astrocytes induced persistently higher levels of chemokines (CXCL10 and CXCL1) under normal conditions but subdued astroglial and microglial activation after 3 weeks of cuprizone intoxication (Petković, Campbell, Gonzalez, & Castellano, 2016). Consistent with blunted Il-1b and Il-6 production in CYM5442-treated mice during the early phase of cuprizone intoxication, CYM5442 also prevented the upregulation of chemokine Cxcl10 (Figure 5c), a key microglial chemoattractant that is primarily produced by reactive astrocytes as ablation of Cxcl10 gene significantly prevented early microglial activation .…”

Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure

“…Proper regulation and control of the inflammatory response is required to protect OLs from damage and to promote remyelination (Diemel, Copelman, & Cuzner, 1998;Marriott et al, 2008;Merson, Binder, & Kilpatrick, 2010;Petković, Campbell, Gonzalez, & Castellano, 2016). In demyelinating diseases such as MS, alterations in the innate immune system contribute to myelin damage, axonal loss and limit remyelination (Podbielska, Banik, Kurowska, & Hogan, 2013).…”

Commentary: Mycoplasma pneumoniae-associated mild encephalitis/encephalopathy with a reversible splenial lesion: Report of two pediatric cases and a comprehensive literature review

“…TNF-α and IL-1β) and ROS in microglial cells 40 . Transgenic mice with astrocyte-targeted production of IL-6 showed inefficient removal of demyelinating stimulus-induced degraded myelin and axonal protection in the CC compared to wild type mice 41 , suggesting that IL-6 may impair myelin maintenance and induce axonal injury. In children infected with M.pneumoniae, toll-like receptor (TRL)2 and TRL4, which are expressed in the CC 42,43 , were increased 44 .…”