IFNγ Enhances Microglial Reactions to Hippocampal Axonal Degeneration

Jensen, Marina Bergen; Hegelund, I.V.; Lomholt, Nina D.; Finsen, Bente; Owens, Trevor

doi:10.1523/jneurosci.20-10-03612.2000

Cited by 70 publications

(68 citation statements)

References 73 publications

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“…98,99 Using the PP lesion model, our group has previously demonstrated a transient increase in TNF mRNA expression levels at 2 days post lesion, 34 which was increased by the presence of IFN-␥. 100 This was confirmed in the present study, in which a marked increase in TNF mRNA expression was observed in T PLP mice at 2 days post lesion and persisted at 7 days post lesion. Microglial production of TNF has been previously associated with increased phagocytosis of myelin debris in microglia in vitro.…”

Section: Discussionsupporting

confidence: 91%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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In multiple sclerosis (MS), myelin-specific T cells are normally associated with destruction of myelin and axonal damage. However, in acute MS plaque, remyelination occurs concurrent with T-cell infiltration, which raises the question of whether T cells might stimulate myelin repair. We investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early after induction via axonal transection, resulting in a 25% increase in the numbers of oligodendrocytes. In contrast, T cells specific for ovalbumin did not stimulate the formation of new oligodendrocytes. In addition, infiltration of myelinspecific T cells enhanced the sprouting response of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system. T cell infiltration, demyelination, and axonal damage are central pathologic features of multiple sclerosis (MS). Whereas the primary immune attack on oligodendrocytes and myelin is effected by T cells, 1,2 remyelination occurs in acute plaques, also in the presence of T cells. 3,4 Remyelination depends on chondroitin sulfate NG2-expressing adult oligodendrocyte precursor cells (OPCs). 5,6 OPCs retain the capacity to proliferate and differentiate into myelinating oligodendrocytes in response to toxic or inflammatory demyelination 7-9 and other forms of central nervous system (CNS) injury such as ischemia, 10 spinal cord injury, 11,12 axonal lesions, 13,14 and inflammation. 15 During differentiation, OPCs downregulate NG2 as cells acquire markers of mature oligodendrocytes such as 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNP). 16 The axonal damage that occurs within and distal to the acute MS lesion can be modeled in the hippocampal dentate gyrus by transection of the perforant pathway (PP), resulting in degeneration of the PP axons and their myelin sheaths in the outer part of the molecular layer. [17][18][19] PP lesions also induce proliferation of OPCs, which results in formation of new oligodendrocytes. 14 These newly formed oligodendrocytes are presumed to myelinate the axonal sprouts that extend from other afferent fiber systems in the dentate gyrus 20,21 such as the associational/commissural afferents from the calretinergic hilar mossy cells. 20,22,23 Indeed, in stratum radiatum of the hippocampal CA3 region, lesion-induced axonal sprouting is associated with formation of more oligodendrocytes and more myelin. 24 Because remyelination ultimately fails in MS, 25 it is assumed that autoimmune demyelination reduces the capacity for myelin repair. 26,27 We investigated the effect of myelin-specific T cells on the formation of oligodendrocytes in the dentate gyrus of ...

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Section: Discussionsupporting

confidence: 91%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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“…Previous studies identified microglia and astrocytes as a prominent source of CCL2 (17). IL-1b and TNF are also glial derived (37,38), and we must assume that the leukocyte contribution was not significant in this case. The differences in effect on CXCL10 may reflect involvement of adjuvant in the EAE model or other differences between these systems.…”

Section: Discussionmentioning

confidence: 64%

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

Khorooshi

Owens

2010

The Journal of Immunology

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Innate glial response is critical for the induction of inflammatory mediators and recruitment of leukocytes to sites of the injury in the CNS. We have examined the involvement of type I IFN signaling in the mouse hippocampus following sterile injury (transection of entorhinal afferents). Type I IFNs signal through a receptor (IFNAR), which involves activation of IFN regulatory factor (IRF)9, leading to the induction of IFN-stimulated genes including IRF7, that in turn enhances the induction of type I IFN. Axonal transection induced upregulation of IRF7 and IRF9 in hippocampus. Induction of IRF7 and IRF9 mRNAs was IFNAR dependent. Double-labeling immunofluorescence showed that IRF7 selectively was induced in Mac-1/CD11b+ macrophages/microglia in hippocampus after axonal transection. IRF7 mRNA was also detected in microglia sorted by flow cytometry. Lack of type I IFN signaling resulted in increased leukocyte infiltration into the lesion-reactive hippocampus. Axonal lesion-induced CXCL10 gene expression was abrogated, whereas matrix metalloproteinase 9 mRNA was elevated in IFNAR-deficient mice. Our findings point to a role for type I IFN signaling in regulation of CNS response to sterile injury.

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“…IFNg could participate in an inflammatory cascade that would also include the activation of microglial cells, as IFNg has been shown to enhance microglial cell activity in vivo. 41 Whether IFNg directly activates microglial cells or mediates astrocytic-dependent microglia activation remains to be determined. Moreover, activated microglia could participate with reactive astrocytes in the chronic production of neurotoxic molecules that could function through different mechanisms in different motoneuron populations (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

et al. 2010

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that primarily affects motoneurons in the brain and spinal cord. Dominant mutations in superoxide dismutase-1 (SOD1) cause a familial form of ALS. Mutant SOD1-damaged glial cells contribute to ALS pathogenesis by releasing neurotoxic factors, but the mechanistic basis of the motoneuron-specific elimination is poorly understood. Here, we describe a motoneuron-selective death pathway triggered by activation of lymphotoxin-b receptor (LT-bR) by LIGHT, and operating by a novel signaling scheme. We show that astrocytes expressing mutant SOD1 mediate the selective death of motoneurons through the proinflammatory cytokine interferon-c (IFNc), which activates the LIGHT-LT-bR death pathway. The expression of LIGHT and LT-bR by motoneurons in vivo correlates with the preferential expression of IFNc by motoneurons and astrocytes at disease onset and symptomatic stage in ALS mice. Importantly, the genetic ablation of Light in an ALS mouse model retards progression, but not onset, of the disease and increases lifespan. We propose that IFNc contributes to a cross-talk between motoneurons and astrocytes causing the selective loss of some motoneurons following activation of the LIGHT-induced death pathway.

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IFNγ Enhances Microglial Reactions to Hippocampal Axonal Degeneration

Cited by 70 publications

References 73 publications

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

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