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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 stimulated opposite responses in Atm+/+ and Atm−/− frontal cortexes. Cyclin A (A–D), γ-H2AX (E–H), cleaved caspase 3 (I–L) and nuclear HDAC4 (M–P) were measured after LPS or cytokine injection. ATM deficiency significantly increasedγ-H2AX in PCs (R). LPS treatment failed to significantly increase the expression of all markers (B, F, J, N). TNFα reduced γ-H2AX (G), whereas IL1β increased it (H). By contrast TNFα had little effect on cyclin A (C) or HDAC4 nuclear localization (O), whereas IL1β increased both (D, P) in Atm−/− and Atm+/+frontal cortex (M–P). Cleaved caspase 3 signals were similar in all treatment groups (I–L). White arrows indicate neurons with respective damage markers. Scale bar, 50 µm. n = 3 for each group.
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Figure 4: TNFα and IL1β stimulated opposite responses in Atm+/+ and Atm−/− frontal cortexes. Cyclin A (A–D), γ-H2AX (E–H), cleaved caspase 3 (I–L) and nuclear HDAC4 (M–P) were measured after LPS or cytokine injection. ATM deficiency significantly increasedγ-H2AX in PCs (R). LPS treatment failed to significantly increase the expression of all markers (B, F, J, N). TNFα reduced γ-H2AX (G), whereas IL1β increased it (H). By contrast TNFα had little effect on cyclin A (C) or HDAC4 nuclear localization (O), whereas IL1β increased both (D, P) in Atm−/− and Atm+/+frontal cortex (M–P). Cleaved caspase 3 signals were similar in all treatment groups (I–L). White arrows indicate neurons with respective damage markers. Scale bar, 50 µm. n = 3 for each group.

Mentions: Similar to cerebellum, ATM deficiency directly induced cellular damage in cortical neurons as shown by cyclin A (Fig. 4Q), γ-H2AX (Fig. 4R), and HDAC4 (Fig. 4T). Although LPS-induced inflammation has effects in both cortex and cerebellum, the cells in two areas respond differently. In frontal cortex, LPS failed to increase evidence for neuronal cell-cycle reentry (Fig. 4B,Q), DNA damage (Fig. 4F,R), cell death (Fig. 4J,S), or nuclear translocation of HDAC4 (Fig. 4N,T) in both genotypes. This contrasts sharply with the situation in cerebellum where LPS-induced inflammation leads to a substantial increase in Purkinje cell-cycle activity (Yang et al., 2014). Similar to the findings in cerebellum, TNFα failed to accelerate the ATM deficiency-induced damage in both Atm+/+ (Fig. 4Q–T) and Atm−/−neocortex (Fig. 4C,G,K,O); once again the trend for this single cytokine was in the direction of improvement (Fig. 4R,T). To our surprise, whereas LPS treatment induced few significant changes in frontal cortex, direct injection of IL1β caused multiple deleterious changes. Although the change is not obvious in Atm+/+neocortex (Fig. 4Q,R,T), cyclin A (Fig. 4D), and γ-H2AX (Fig. 4H) expression significantly increased, whereas nuclear HDAC4 (Fig. 4P) expression showed increased trend in IL1β-treated Atm−/− frontal cortex (Fig. 4Q,R,T). There was no evidence for enhanced cell death (cleaved caspase-3 staining) in any of the treatment groups (Fig. 4J–L,S).


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 stimulated opposite responses in Atm+/+ and Atm−/− frontal cortexes. Cyclin A (A–D), γ-H2AX (E–H), cleaved caspase 3 (I–L) and nuclear HDAC4 (M–P) were measured after LPS or cytokine injection. ATM deficiency significantly increasedγ-H2AX in PCs (R). LPS treatment failed to significantly increase the expression of all markers (B, F, J, N). TNFα reduced γ-H2AX (G), whereas IL1β increased it (H). By contrast TNFα had little effect on cyclin A (C) or HDAC4 nuclear localization (O), whereas IL1β increased both (D, P) in Atm−/− and Atm+/+frontal cortex (M–P). Cleaved caspase 3 signals were similar in all treatment groups (I–L). White arrows indicate neurons with respective damage markers. 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 4: TNFα and IL1β stimulated opposite responses in Atm+/+ and Atm−/− frontal cortexes. Cyclin A (A–D), γ-H2AX (E–H), cleaved caspase 3 (I–L) and nuclear HDAC4 (M–P) were measured after LPS or cytokine injection. ATM deficiency significantly increasedγ-H2AX in PCs (R). LPS treatment failed to significantly increase the expression of all markers (B, F, J, N). TNFα reduced γ-H2AX (G), whereas IL1β increased it (H). By contrast TNFα had little effect on cyclin A (C) or HDAC4 nuclear localization (O), whereas IL1β increased both (D, P) in Atm−/− and Atm+/+frontal cortex (M–P). Cleaved caspase 3 signals were similar in all treatment groups (I–L). White arrows indicate neurons with respective damage markers. Scale bar, 50 µm. n = 3 for each group.
Mentions: Similar to cerebellum, ATM deficiency directly induced cellular damage in cortical neurons as shown by cyclin A (Fig. 4Q), γ-H2AX (Fig. 4R), and HDAC4 (Fig. 4T). Although LPS-induced inflammation has effects in both cortex and cerebellum, the cells in two areas respond differently. In frontal cortex, LPS failed to increase evidence for neuronal cell-cycle reentry (Fig. 4B,Q), DNA damage (Fig. 4F,R), cell death (Fig. 4J,S), or nuclear translocation of HDAC4 (Fig. 4N,T) in both genotypes. This contrasts sharply with the situation in cerebellum where LPS-induced inflammation leads to a substantial increase in Purkinje cell-cycle activity (Yang et al., 2014). Similar to the findings in cerebellum, TNFα failed to accelerate the ATM deficiency-induced damage in both Atm+/+ (Fig. 4Q–T) and Atm−/−neocortex (Fig. 4C,G,K,O); once again the trend for this single cytokine was in the direction of improvement (Fig. 4R,T). To our surprise, whereas LPS treatment induced few significant changes in frontal cortex, direct injection of IL1β caused multiple deleterious changes. Although the change is not obvious in Atm+/+neocortex (Fig. 4Q,R,T), cyclin A (Fig. 4D), and γ-H2AX (Fig. 4H) expression significantly increased, whereas nuclear HDAC4 (Fig. 4P) expression showed increased trend in IL1β-treated Atm−/− frontal cortex (Fig. 4Q,R,T). There was no evidence for enhanced cell death (cleaved caspase-3 staining) in any of the treatment groups (Fig. 4J–L,S).

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