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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

p38 MAP kinase phosphorylation level varied across treatment groups. p38 phosphorylation levels were significantly induced in wild-type cerebellum and cortex following LPS treatment (A, D). Quantification showed high variability across each animal (B, E). Phospho-p38 immunohistochemistry confirmed the Western results (G, H, O, P, W, X). Atm−/−neurons had increased phospho-p38 levels in both cerebellum and cortex (G, K, O, S); quantification confirmed (W, X). LPS reduced phospho-p38 levels in Atm−/− cortex as shown by Western blot (D, F) and immunohistochemistry (S, T, X) but had no effects on Atm−/− cerebellum (A, C, K, L, W). IL1β induced p38 phosphorylation in Atm−/− Purkinje cells (K, N, W). White arrows indicate neurons with nuclear phospho-p38. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 5 for wild-type animals and n = 3 for Atm-/- animals.
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Figure 5: p38 MAP kinase phosphorylation level varied across treatment groups. p38 phosphorylation levels were significantly induced in wild-type cerebellum and cortex following LPS treatment (A, D). Quantification showed high variability across each animal (B, E). Phospho-p38 immunohistochemistry confirmed the Western results (G, H, O, P, W, X). Atm−/−neurons had increased phospho-p38 levels in both cerebellum and cortex (G, K, O, S); quantification confirmed (W, X). LPS reduced phospho-p38 levels in Atm−/− cortex as shown by Western blot (D, F) and immunohistochemistry (S, T, X) but had no effects on Atm−/− cerebellum (A, C, K, L, W). IL1β induced p38 phosphorylation in Atm−/− Purkinje cells (K, N, W). White arrows indicate neurons with nuclear phospho-p38. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 5 for wild-type animals and n = 3 for Atm-/- animals.

Mentions: The cytokine signaling pathway has been linked to the activation of the MAP kinases. To explore the mechanism(s) behind the inflammatory responses in cortex and cerebellum we used Western blot analysis and immunohistochemistry to examine both total levels and the phosphorylation status of the various components of this system. The p38 kinase is generally viewed as being elevated during neurodegeneration. Not surprisingly, therefore, on Western blots of wild-type neocortex, the levels of p38 phosphorylation trended higher after LPS treatment (Fig. 5D,E). Quantification of immunostained tissue (Fig. 5O–R,X) led to a similar conclusion. Neither of the individual cytokines appeared to have an effect but the high variability across animals may have precluded some results from reaching statistical significance. In cerebellum, we found no detectable change on Western blot (Fig. 5A,B), but the results were similar when viewed with Purkinje cell immunohistochemistry (Fig. 5G–J,W).


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

Hui CW, Herrup K - eNeuro (2015)

p38 MAP kinase phosphorylation level varied across treatment groups. p38 phosphorylation levels were significantly induced in wild-type cerebellum and cortex following LPS treatment (A, D). Quantification showed high variability across each animal (B, E). Phospho-p38 immunohistochemistry confirmed the Western results (G, H, O, P, W, X). Atm−/−neurons had increased phospho-p38 levels in both cerebellum and cortex (G, K, O, S); quantification confirmed (W, X). LPS reduced phospho-p38 levels in Atm−/− cortex as shown by Western blot (D, F) and immunohistochemistry (S, T, X) but had no effects on Atm−/− cerebellum (A, C, K, L, W). IL1β induced p38 phosphorylation in Atm−/− Purkinje cells (K, N, W). White arrows indicate neurons with nuclear phospho-p38. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. 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 5: p38 MAP kinase phosphorylation level varied across treatment groups. p38 phosphorylation levels were significantly induced in wild-type cerebellum and cortex following LPS treatment (A, D). Quantification showed high variability across each animal (B, E). Phospho-p38 immunohistochemistry confirmed the Western results (G, H, O, P, W, X). Atm−/−neurons had increased phospho-p38 levels in both cerebellum and cortex (G, K, O, S); quantification confirmed (W, X). LPS reduced phospho-p38 levels in Atm−/− cortex as shown by Western blot (D, F) and immunohistochemistry (S, T, X) but had no effects on Atm−/− cerebellum (A, C, K, L, W). IL1β induced p38 phosphorylation in Atm−/− Purkinje cells (K, N, W). White arrows indicate neurons with nuclear phospho-p38. GC, Granule cell layer; ML, molecular layer. Scale bar, 50 µm. n = 5 for wild-type animals and n = 3 for Atm-/- animals.
Mentions: The cytokine signaling pathway has been linked to the activation of the MAP kinases. To explore the mechanism(s) behind the inflammatory responses in cortex and cerebellum we used Western blot analysis and immunohistochemistry to examine both total levels and the phosphorylation status of the various components of this system. The p38 kinase is generally viewed as being elevated during neurodegeneration. Not surprisingly, therefore, on Western blots of wild-type neocortex, the levels of p38 phosphorylation trended higher after LPS treatment (Fig. 5D,E). Quantification of immunostained tissue (Fig. 5O–R,X) led to a similar conclusion. Neither of the individual cytokines appeared to have an effect but the high variability across animals may have precluded some results from reaching statistical significance. In cerebellum, we found no detectable change on Western blot (Fig. 5A,B), but the results were similar when viewed with Purkinje cell immunohistochemistry (Fig. 5G–J,W).

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