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Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination.

Hisahara S, Yuan J, Momoi T, Okano H, Miura M - J. Exp. Med. (2001)

Bottom Line: Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE.Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions.EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroanatomy, Department of Neuroscience, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

ABSTRACT
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

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Caspase-11–deficient mice are less susceptible to EAE induction. (A) Daily mean clinical course and severity of the EAE induced by MOG35–55 peptide for each genotype. Clinical signs of the disease were monitored daily, beginning on day 7, and were graded on a scale from 0 to 6. (B) Immunohistochemical staining of the white matter of the lumbar spinal cord with anti-πGST and anti-activated caspase-3 antibodies in caspase-11−/− mice in adjacent thin sections. Nuclear staining using Hoechst 33342 was also performed. Note that the numbers of both activated caspase-3–positive OLGs were markedly less in caspase-11−/− mice than in wild-type mice with grade 4 EAE. Compare with the similar staining of wild type (Fig. 2 A). Arrows indicate OLGs that express activated caspase-3. Bars: 20 μm. (C) The percentage of activated caspase-3–positive cells and the percentage of apoptotic OLGs in wild-type versus caspase-11−/− mice 20 d after immunization. Data give the percentage of activated caspase-3–positive cells of the total number of OLGs, the percentage of apoptotic nuclear OLGs of the total number of OLGs, and the percentage of cells showing apoptotic nuclear features of the total number of activated caspase-3–positive OLGs counted in three independent visual fields selected in a blind manner. Values are means ± SEM (error bars).
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Figure 4: Caspase-11–deficient mice are less susceptible to EAE induction. (A) Daily mean clinical course and severity of the EAE induced by MOG35–55 peptide for each genotype. Clinical signs of the disease were monitored daily, beginning on day 7, and were graded on a scale from 0 to 6. (B) Immunohistochemical staining of the white matter of the lumbar spinal cord with anti-πGST and anti-activated caspase-3 antibodies in caspase-11−/− mice in adjacent thin sections. Nuclear staining using Hoechst 33342 was also performed. Note that the numbers of both activated caspase-3–positive OLGs were markedly less in caspase-11−/− mice than in wild-type mice with grade 4 EAE. Compare with the similar staining of wild type (Fig. 2 A). Arrows indicate OLGs that express activated caspase-3. Bars: 20 μm. (C) The percentage of activated caspase-3–positive cells and the percentage of apoptotic OLGs in wild-type versus caspase-11−/− mice 20 d after immunization. Data give the percentage of activated caspase-3–positive cells of the total number of OLGs, the percentage of apoptotic nuclear OLGs of the total number of OLGs, and the percentage of cells showing apoptotic nuclear features of the total number of activated caspase-3–positive OLGs counted in three independent visual fields selected in a blind manner. Values are means ± SEM (error bars).

Mentions: To further explore the role of caspase-11 in the progression of EAE, we studied the susceptibility of caspase-11−/− mice to MOG peptide–induced EAE. Most wild-type mice develop severe hind limb paralysis 20 d after rat MOG35–55 peptide immunization (Fig. 4 A). The incidence of EAE in control mice was 90% (9/10), with a mean peak of clinical severity of grade 3.8 ± 0.4 (see Materials and Methods, Induction and Assessment of EAE). However, the incidence and severity of EAE in caspase-11−/− mice were significantly reduced (21% incidence, 3/14; severity: 0.679 ± 0.428; P < 0.001). We performed immunohistochemistry with anti-πGST and anti-activated caspase-3 antibodies on the lumbar spinal cord from a caspase-11−/− mouse at 20 d after immunization. The number of activated caspase-3–expressing OLGs was <50% of a wild-type mouse (Fig. 4B and Fig. c). There were very few apoptotic OLGs in the white matter of the caspase-11−/− mouse, as determined using Hoechst 33342 staining. Only <1% of OLGs showed apoptotic and expressed activated caspase-3 (Fig. 4 C). Taken together, these results indicate that caspase-11 plays a significant role in the susceptibility of OLGs to EAE induction.


Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination.

Hisahara S, Yuan J, Momoi T, Okano H, Miura M - J. Exp. Med. (2001)

Caspase-11–deficient mice are less susceptible to EAE induction. (A) Daily mean clinical course and severity of the EAE induced by MOG35–55 peptide for each genotype. Clinical signs of the disease were monitored daily, beginning on day 7, and were graded on a scale from 0 to 6. (B) Immunohistochemical staining of the white matter of the lumbar spinal cord with anti-πGST and anti-activated caspase-3 antibodies in caspase-11−/− mice in adjacent thin sections. Nuclear staining using Hoechst 33342 was also performed. Note that the numbers of both activated caspase-3–positive OLGs were markedly less in caspase-11−/− mice than in wild-type mice with grade 4 EAE. Compare with the similar staining of wild type (Fig. 2 A). Arrows indicate OLGs that express activated caspase-3. Bars: 20 μm. (C) The percentage of activated caspase-3–positive cells and the percentage of apoptotic OLGs in wild-type versus caspase-11−/− mice 20 d after immunization. Data give the percentage of activated caspase-3–positive cells of the total number of OLGs, the percentage of apoptotic nuclear OLGs of the total number of OLGs, and the percentage of cells showing apoptotic nuclear features of the total number of activated caspase-3–positive OLGs counted in three independent visual fields selected in a blind manner. Values are means ± SEM (error bars).
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Figure 4: Caspase-11–deficient mice are less susceptible to EAE induction. (A) Daily mean clinical course and severity of the EAE induced by MOG35–55 peptide for each genotype. Clinical signs of the disease were monitored daily, beginning on day 7, and were graded on a scale from 0 to 6. (B) Immunohistochemical staining of the white matter of the lumbar spinal cord with anti-πGST and anti-activated caspase-3 antibodies in caspase-11−/− mice in adjacent thin sections. Nuclear staining using Hoechst 33342 was also performed. Note that the numbers of both activated caspase-3–positive OLGs were markedly less in caspase-11−/− mice than in wild-type mice with grade 4 EAE. Compare with the similar staining of wild type (Fig. 2 A). Arrows indicate OLGs that express activated caspase-3. Bars: 20 μm. (C) The percentage of activated caspase-3–positive cells and the percentage of apoptotic OLGs in wild-type versus caspase-11−/− mice 20 d after immunization. Data give the percentage of activated caspase-3–positive cells of the total number of OLGs, the percentage of apoptotic nuclear OLGs of the total number of OLGs, and the percentage of cells showing apoptotic nuclear features of the total number of activated caspase-3–positive OLGs counted in three independent visual fields selected in a blind manner. Values are means ± SEM (error bars).
Mentions: To further explore the role of caspase-11 in the progression of EAE, we studied the susceptibility of caspase-11−/− mice to MOG peptide–induced EAE. Most wild-type mice develop severe hind limb paralysis 20 d after rat MOG35–55 peptide immunization (Fig. 4 A). The incidence of EAE in control mice was 90% (9/10), with a mean peak of clinical severity of grade 3.8 ± 0.4 (see Materials and Methods, Induction and Assessment of EAE). However, the incidence and severity of EAE in caspase-11−/− mice were significantly reduced (21% incidence, 3/14; severity: 0.679 ± 0.428; P < 0.001). We performed immunohistochemistry with anti-πGST and anti-activated caspase-3 antibodies on the lumbar spinal cord from a caspase-11−/− mouse at 20 d after immunization. The number of activated caspase-3–expressing OLGs was <50% of a wild-type mouse (Fig. 4B and Fig. c). There were very few apoptotic OLGs in the white matter of the caspase-11−/− mouse, as determined using Hoechst 33342 staining. Only <1% of OLGs showed apoptotic and expressed activated caspase-3 (Fig. 4 C). Taken together, these results indicate that caspase-11 plays a significant role in the susceptibility of OLGs to EAE induction.

Bottom Line: Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE.Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions.EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroanatomy, Department of Neuroscience, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

ABSTRACT
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

Show MeSH
Related in: MedlinePlus