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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

MAP kinase levels in the cerebellum and frontal cortex after different inflammatory challenges. In cerebellum, phosphorylation levels of JNK trended lower after inflammatory stimuli (A, B). This effect was enhanced in Atm−/−, where LPS significantly reduced the levels of phospho-JNK (D, E). In cortex, the reverse situation was found. Phospho-JNK decreased significantly in wild-type after immune challenge (G, H), whereas in Atm−/− phospho-JNK only trended lower after LPS. In both regions and both genotypes, the levels of ERK phosphorylation were largely unchanged after an immune stimulus (C, F, I, L). n = 5 for wild-type animals and n = 3 for Atm−/− animals.
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Figure 6: MAP kinase levels in the cerebellum and frontal cortex after different inflammatory challenges. In cerebellum, phosphorylation levels of JNK trended lower after inflammatory stimuli (A, B). This effect was enhanced in Atm−/−, where LPS significantly reduced the levels of phospho-JNK (D, E). In cortex, the reverse situation was found. Phospho-JNK decreased significantly in wild-type after immune challenge (G, H), whereas in Atm−/− phospho-JNK only trended lower after LPS. In both regions and both genotypes, the levels of ERK phosphorylation were largely unchanged after an immune stimulus (C, F, I, L). n = 5 for wild-type animals and n = 3 for Atm−/− animals.

Mentions: ERK and JNK phosphorylation levels were also investigated. Immunohistochemical findings with the phospho-specific antibodies proved unsatisfactory, and so we restricted our analysis to Western blots. Phosphorylation levels of ERK were similar among the treatment groups in both genotypes and both brain regions (Fig. 6, right, quantification in the histograms). By contrast JNK phosphorylation was sensitive to genotype and brain region, as well as to the nature of the immune challenge. The mutant–wild-type difference could be seen in the response to the LPS injections; a nearly 75% drop in phospho-JNK in mutant cerebellum with virtually no change in wild-type cerebellum (Fig. 6B and E, respectively). The brain region difference was also apparent after LPS injection. Although there was a 75% drop in phospho-JNK levels in mutant cerebellum, there was only a trend towards lower levels in mutant cortex (Fig. 6E,K). The results of the TNFα injection led to similar conclusions (Fig. 6B,H). Finally, we found that the response of wild-type cortex most clearly highlighted the differences among the immune challenges; both TNFα (p < 0.05) and IL1β (p = 0.069) suppressed phospho-JNK (Fig. 6G,H), whereas LPS induced no significant change in the two regions.


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

Hui CW, Herrup K - eNeuro (2015)

MAP kinase levels in the cerebellum and frontal cortex after different inflammatory challenges. In cerebellum, phosphorylation levels of JNK trended lower after inflammatory stimuli (A, B). This effect was enhanced in Atm−/−, where LPS significantly reduced the levels of phospho-JNK (D, E). In cortex, the reverse situation was found. Phospho-JNK decreased significantly in wild-type after immune challenge (G, H), whereas in Atm−/− phospho-JNK only trended lower after LPS. In both regions and both genotypes, the levels of ERK phosphorylation were largely unchanged after an immune stimulus (C, F, I, L). n = 5 for wild-type animals and n = 3 for Atm−/− animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: MAP kinase levels in the cerebellum and frontal cortex after different inflammatory challenges. In cerebellum, phosphorylation levels of JNK trended lower after inflammatory stimuli (A, B). This effect was enhanced in Atm−/−, where LPS significantly reduced the levels of phospho-JNK (D, E). In cortex, the reverse situation was found. Phospho-JNK decreased significantly in wild-type after immune challenge (G, H), whereas in Atm−/− phospho-JNK only trended lower after LPS. In both regions and both genotypes, the levels of ERK phosphorylation were largely unchanged after an immune stimulus (C, F, I, L). n = 5 for wild-type animals and n = 3 for Atm−/− animals.
Mentions: ERK and JNK phosphorylation levels were also investigated. Immunohistochemical findings with the phospho-specific antibodies proved unsatisfactory, and so we restricted our analysis to Western blots. Phosphorylation levels of ERK were similar among the treatment groups in both genotypes and both brain regions (Fig. 6, right, quantification in the histograms). By contrast JNK phosphorylation was sensitive to genotype and brain region, as well as to the nature of the immune challenge. The mutant–wild-type difference could be seen in the response to the LPS injections; a nearly 75% drop in phospho-JNK in mutant cerebellum with virtually no change in wild-type cerebellum (Fig. 6B and E, respectively). The brain region difference was also apparent after LPS injection. Although there was a 75% drop in phospho-JNK levels in mutant cerebellum, there was only a trend towards lower levels in mutant cortex (Fig. 6E,K). The results of the TNFα injection led to similar conclusions (Fig. 6B,H). Finally, we found that the response of wild-type cortex most clearly highlighted the differences among the immune challenges; both TNFα (p < 0.05) and IL1β (p = 0.069) suppressed phospho-JNK (Fig. 6G,H), whereas LPS induced no significant change in the two regions.

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