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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

Expression patterns of anti-inflammation associated genes and monocyte infiltration following cytokine stimulation. In wild-type and Atm−/− mouse cortex, LPS administration significantly triggered the expression of Ym1 (A), p21 (B), Tgfβ1 (C), Cd45 (D), and Trem2 (E); with the exception of a modest change in p21 expression in wild-type, the individual cytokines were without effect. TNFα specifically suppressed Cd45 (D) and Trem2 (E) in cerebellum of both genotypes. Similar patterns were observed by CD45 protein expression (F–U). *p < 0.05; **p < 0.01; ***p < 0.001 between cortex and cerebellum in the same treatment group; #p < 0.05; ##p < 0.01; ###p < 0.001 between the values of LPS/cytokine treated and the respective saline-treated cortex or cerebellum groups. Scale bar, 50 µm. n = 3 for each group.
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Figure 7: Expression patterns of anti-inflammation associated genes and monocyte infiltration following cytokine stimulation. In wild-type and Atm−/− mouse cortex, LPS administration significantly triggered the expression of Ym1 (A), p21 (B), Tgfβ1 (C), Cd45 (D), and Trem2 (E); with the exception of a modest change in p21 expression in wild-type, the individual cytokines were without effect. TNFα specifically suppressed Cd45 (D) and Trem2 (E) in cerebellum of both genotypes. Similar patterns were observed by CD45 protein expression (F–U). *p < 0.05; **p < 0.01; ***p < 0.001 between cortex and cerebellum in the same treatment group; #p < 0.05; ##p < 0.01; ###p < 0.001 between the values of LPS/cytokine treated and the respective saline-treated cortex or cerebellum groups. Scale bar, 50 µm. n = 3 for each group.

Mentions: The highly variable nature of these responses led us to ask whether a compensatory response of the network of anti-inflammatory genes might be involved. We focused on this hypothesis because we reasoned that if cells were delicately balanced between a pro- and anti-inflammatory phenotype, one would predict exactly the type of variability that we observe. To explore this possibility we used q-PCR to examine the expression of three genes associated with the anti-inflammatory state (also known as M2); Ym1, p21, and Tgfβ1 (Fig. 7A–C). Given the sensitivity of the system to Atm genotype, we were surprised to find that the levels of all three genes were unchanged in the untreated mutant brains. Yet when we compared the expression responses of the three to the various immune challenges, we found a broadly similar pattern. LPS induced a significant response in all three genes; the single cytokines were far less effective. Ym1 and p21 were far more sensitive in Atm−/− than in wild-type brain and cortex was more responsive to LPS than cerebellum. Tgfβ1 was sensitive in both genotypes and both regions (albeit with an enhanced response in wild-type cortex). To discriminate between the contribution of microglia and circulating monocytes to M2 phenotype, gene and protein expression of Cd45 (a peripheral monocyte marker) was investigated by q-PCR and immunohistochemistry. At the same time, expression of the monocyte specific anti-inflammatory gene Trem2 (triggering receptor expressed on myeloid cells 2) was also investigated. Although expression of the two genes was lower in cerebellum than cortex, the levels were unchanged in the untreated mutant brains (Fig. 7D–F). Significantly, LPS induced the infiltration of circulating monocytes in both brain regions of both genotypes as revealed by increased CD45 gene (Fig. 7D) and protein (Fig. 7G,K,O,S) expression. Similar responses were observed for Trem2 (Fig. 7E). No single cytokine induced infiltration of peripheral monocytes while TNFα reduced gene (Cd45 and Trem2) and protein (CD45) expression (Fig. 7D,E,P,T) in cerebellum but not in cortex of both genotypes.


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

Hui CW, Herrup K - eNeuro (2015)

Expression patterns of anti-inflammation associated genes and monocyte infiltration following cytokine stimulation. In wild-type and Atm−/− mouse cortex, LPS administration significantly triggered the expression of Ym1 (A), p21 (B), Tgfβ1 (C), Cd45 (D), and Trem2 (E); with the exception of a modest change in p21 expression in wild-type, the individual cytokines were without effect. TNFα specifically suppressed Cd45 (D) and Trem2 (E) in cerebellum of both genotypes. Similar patterns were observed by CD45 protein expression (F–U). *p < 0.05; **p < 0.01; ***p < 0.001 between cortex and cerebellum in the same treatment group; #p < 0.05; ##p < 0.01; ###p < 0.001 between the values of LPS/cytokine treated and the respective saline-treated cortex or cerebellum groups. Scale bar, 50 µm. n = 3 for each group.
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Figure 7: Expression patterns of anti-inflammation associated genes and monocyte infiltration following cytokine stimulation. In wild-type and Atm−/− mouse cortex, LPS administration significantly triggered the expression of Ym1 (A), p21 (B), Tgfβ1 (C), Cd45 (D), and Trem2 (E); with the exception of a modest change in p21 expression in wild-type, the individual cytokines were without effect. TNFα specifically suppressed Cd45 (D) and Trem2 (E) in cerebellum of both genotypes. Similar patterns were observed by CD45 protein expression (F–U). *p < 0.05; **p < 0.01; ***p < 0.001 between cortex and cerebellum in the same treatment group; #p < 0.05; ##p < 0.01; ###p < 0.001 between the values of LPS/cytokine treated and the respective saline-treated cortex or cerebellum groups. Scale bar, 50 µm. n = 3 for each group.
Mentions: The highly variable nature of these responses led us to ask whether a compensatory response of the network of anti-inflammatory genes might be involved. We focused on this hypothesis because we reasoned that if cells were delicately balanced between a pro- and anti-inflammatory phenotype, one would predict exactly the type of variability that we observe. To explore this possibility we used q-PCR to examine the expression of three genes associated with the anti-inflammatory state (also known as M2); Ym1, p21, and Tgfβ1 (Fig. 7A–C). Given the sensitivity of the system to Atm genotype, we were surprised to find that the levels of all three genes were unchanged in the untreated mutant brains. Yet when we compared the expression responses of the three to the various immune challenges, we found a broadly similar pattern. LPS induced a significant response in all three genes; the single cytokines were far less effective. Ym1 and p21 were far more sensitive in Atm−/− than in wild-type brain and cortex was more responsive to LPS than cerebellum. Tgfβ1 was sensitive in both genotypes and both regions (albeit with an enhanced response in wild-type cortex). To discriminate between the contribution of microglia and circulating monocytes to M2 phenotype, gene and protein expression of Cd45 (a peripheral monocyte marker) was investigated by q-PCR and immunohistochemistry. At the same time, expression of the monocyte specific anti-inflammatory gene Trem2 (triggering receptor expressed on myeloid cells 2) was also investigated. Although expression of the two genes was lower in cerebellum than cortex, the levels were unchanged in the untreated mutant brains (Fig. 7D–F). Significantly, LPS induced the infiltration of circulating monocytes in both brain regions of both genotypes as revealed by increased CD45 gene (Fig. 7D) and protein (Fig. 7G,K,O,S) expression. Similar responses were observed for Trem2 (Fig. 7E). No single cytokine induced infiltration of peripheral monocytes while TNFα reduced gene (Cd45 and Trem2) and protein (CD45) expression (Fig. 7D,E,P,T) in cerebellum but not in cortex of both genotypes.

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