Limits...
Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner(1,2,3).

Hui CW, Herrup K - eNeuro (2015)

Bottom Line: Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype.Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway.This implies that management of the immune status of A-T patients might have significant clinical benefit.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong.

ABSTRACT
Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges, such as lipopolysaccharide (LPS) injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit.

No MeSH data available.


Related in: MedlinePlus

TNFα and IL1β produced opposite responses on cerebellar Purkinje cells in Atm+/+ and Atm−/−animals. Cyclin A (A–C), γ-H2AX (D, E), cleaved caspase 3 (G–I), and nuclear HDAC4 (J–L) were measured after cytokine injection. ATM deficiency induced increase in these markers in Purkinje cells (PCs; M–P). TNFα significantly reduced cyclin A in Atm+/+PCs (M) and γ-H2AX in Atm−/−PCs (D, E), whereas IL1β significantly induced cyclin A (A, C, M) and HDAC4 nuclear translocation (J, L, P). TNFa had no effect or slightly reduced these markers in Atm−/−PCs. Quantification confirmed these findings (M, N, P). Cleaved caspase 3 signals were similar in all treatment groups (G–I, O). White arrows indicate PCs with respective damage markers. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4596028&req=5

Figure 2: TNFα and IL1β produced opposite responses on cerebellar Purkinje cells in Atm+/+ and Atm−/−animals. Cyclin A (A–C), γ-H2AX (D, E), cleaved caspase 3 (G–I), and nuclear HDAC4 (J–L) were measured after cytokine injection. ATM deficiency induced increase in these markers in Purkinje cells (PCs; M–P). TNFα significantly reduced cyclin A in Atm+/+PCs (M) and γ-H2AX in Atm−/−PCs (D, E), whereas IL1β significantly induced cyclin A (A, C, M) and HDAC4 nuclear translocation (J, L, P). TNFa had no effect or slightly reduced these markers in Atm−/−PCs. Quantification confirmed these findings (M, N, P). Cleaved caspase 3 signals were similar in all treatment groups (G–I, O). White arrows indicate PCs with respective damage markers. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.

Mentions: We monitored cellular damage in the cerebella of cytokine-injected Atm+/+ and Atm−/− mice. ATM deficiency led to increased DNA damage in Purkinje cells (Fig. 2N). IL1β largely mimicked LPS-induced degenerative changes in Atm+/+ and Atm−/−Purkinje cells reported by others (Yang et al., 2014), including an increase in cell-cycle events as measured by cyclin A (Fig. 2A,C,M), increased γ-H2AX staining (Fig. 2D,F,N), and epigenetic changes as measured by the nuclear translocation of histone deacetylase 4 (HDAC4; Fig. 2J,L,P). Interestingly, IL1β drove significantly more neurodegeneration in Atm−/−than Atm+/+ Purkinje cells (Fig. 2M–P). Other markers, including cleaved caspase 3 (a cell death marker), were not significantly changed by either TNFα or IL1β within groups with same genotype. Surprisingly, whereas IL1β worsened, TNFα improved the ATM-phenotype in nearly every domain. The effect achieved significance only for DNA damage as measured by cyclin A in Atm+/+ animals (Fig. 2M) and γ-H2AX in Atm−/− animals (Fig. 2D,E,N); however, all four markers showed a trend toward improvement in Atm−/−Purkinje cells. The suggestion is that, in the context of our injection protocol, peripheral TNFα administration has neuroprotective qualities rather than the destructive properties expected of a proinflammatory cytokine. As both cytokines would be expected to increase following an LPS injection, a complex response of brain neurons would be predicted.


Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner(1,2,3).

Hui CW, Herrup K - eNeuro (2015)

TNFα and IL1β produced opposite responses on cerebellar Purkinje cells in Atm+/+ and Atm−/−animals. Cyclin A (A–C), γ-H2AX (D, E), cleaved caspase 3 (G–I), and nuclear HDAC4 (J–L) were measured after cytokine injection. ATM deficiency induced increase in these markers in Purkinje cells (PCs; M–P). TNFα significantly reduced cyclin A in Atm+/+PCs (M) and γ-H2AX in Atm−/−PCs (D, E), whereas IL1β significantly induced cyclin A (A, C, M) and HDAC4 nuclear translocation (J, L, P). TNFa had no effect or slightly reduced these markers in Atm−/−PCs. Quantification confirmed these findings (M, N, P). Cleaved caspase 3 signals were similar in all treatment groups (G–I, O). White arrows indicate PCs with respective damage markers. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596028&req=5

Figure 2: TNFα and IL1β produced opposite responses on cerebellar Purkinje cells in Atm+/+ and Atm−/−animals. Cyclin A (A–C), γ-H2AX (D, E), cleaved caspase 3 (G–I), and nuclear HDAC4 (J–L) were measured after cytokine injection. ATM deficiency induced increase in these markers in Purkinje cells (PCs; M–P). TNFα significantly reduced cyclin A in Atm+/+PCs (M) and γ-H2AX in Atm−/−PCs (D, E), whereas IL1β significantly induced cyclin A (A, C, M) and HDAC4 nuclear translocation (J, L, P). TNFa had no effect or slightly reduced these markers in Atm−/−PCs. Quantification confirmed these findings (M, N, P). Cleaved caspase 3 signals were similar in all treatment groups (G–I, O). White arrows indicate PCs with respective damage markers. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 3 for each group.
Mentions: We monitored cellular damage in the cerebella of cytokine-injected Atm+/+ and Atm−/− mice. ATM deficiency led to increased DNA damage in Purkinje cells (Fig. 2N). IL1β largely mimicked LPS-induced degenerative changes in Atm+/+ and Atm−/−Purkinje cells reported by others (Yang et al., 2014), including an increase in cell-cycle events as measured by cyclin A (Fig. 2A,C,M), increased γ-H2AX staining (Fig. 2D,F,N), and epigenetic changes as measured by the nuclear translocation of histone deacetylase 4 (HDAC4; Fig. 2J,L,P). Interestingly, IL1β drove significantly more neurodegeneration in Atm−/−than Atm+/+ Purkinje cells (Fig. 2M–P). Other markers, including cleaved caspase 3 (a cell death marker), were not significantly changed by either TNFα or IL1β within groups with same genotype. Surprisingly, whereas IL1β worsened, TNFα improved the ATM-phenotype in nearly every domain. The effect achieved significance only for DNA damage as measured by cyclin A in Atm+/+ animals (Fig. 2M) and γ-H2AX in Atm−/− animals (Fig. 2D,E,N); however, all four markers showed a trend toward improvement in Atm−/−Purkinje cells. The suggestion is that, in the context of our injection protocol, peripheral TNFα administration has neuroprotective qualities rather than the destructive properties expected of a proinflammatory cytokine. As both cytokines would be expected to increase following an LPS injection, a complex response of brain neurons would be predicted.

Bottom Line: Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype.Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway.This implies that management of the immune status of A-T patients might have significant clinical benefit.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong.

ABSTRACT
Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges, such as lipopolysaccharide (LPS) injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit.

No MeSH data available.


Related in: MedlinePlus