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

Inflammatory conditions induced by TNFα and IL1β in the cerebellum. TNFα and IL1β triggered microglial activation in both wild-type (A–C) and Atm−/− (D–F). Both cytokines stimulated astrocytic activation in Atm−/− (J–L) but not in wild-type (G–I). GC, Granule cell layer; M, molecular layer. Scale bar, 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Inflammatory conditions induced by TNFα and IL1β in the cerebellum. TNFα and IL1β triggered microglial activation in both wild-type (A–C) and Atm−/− (D–F). Both cytokines stimulated astrocytic activation in Atm−/− (J–L) but not in wild-type (G–I). GC, Granule cell layer; M, molecular layer. Scale bar, 50 µm.

Mentions: LPS (intraperitoneal injection) triggers a complex cytokine “storm”; first in the periphery and then in the CNS. Our A-T mouse model cannot replicate the main neurological deficiency (loss of Purkinje cells) in human patients with A-T (Barlow et al., 1996), and so we attempted to use LPS-induced neuronal damage to mimic the neurological defects in human A-T. Although the reactions to systemic injections are complex, we wished to sort out the role(s) of individual proinflammatory cytokines as mediators of the LPS effect. To do this, we injected wild-type and Atm−/− animals (3 months old) daily with TNFα (70 µg/kg) or IL1β (5 µg/kg) injections for 4 d. As expected, both cytokines triggered the activation of Iba-1-positive microglia in wild-type (Fig. 1A–C) and Atm−/−(Fig. 1D–F) cerebella. When we used GFAP to measure astrocytic activation, however, the cytokines produced evidence of astrogliosis only in Atm-/- but not in wild-type (Fig. 1G–L) cerebella. Although our analysis involved both mutant and wild-type animals, only images from mutants are shown.


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

Hui CW, Herrup K - eNeuro (2015)

Inflammatory conditions induced by TNFα and IL1β in the cerebellum. TNFα and IL1β triggered microglial activation in both wild-type (A–C) and Atm−/− (D–F). Both cytokines stimulated astrocytic activation in Atm−/− (J–L) but not in wild-type (G–I). GC, Granule cell layer; M, molecular layer. Scale bar, 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Inflammatory conditions induced by TNFα and IL1β in the cerebellum. TNFα and IL1β triggered microglial activation in both wild-type (A–C) and Atm−/− (D–F). Both cytokines stimulated astrocytic activation in Atm−/− (J–L) but not in wild-type (G–I). GC, Granule cell layer; M, molecular layer. Scale bar, 50 µm.
Mentions: LPS (intraperitoneal injection) triggers a complex cytokine “storm”; first in the periphery and then in the CNS. Our A-T mouse model cannot replicate the main neurological deficiency (loss of Purkinje cells) in human patients with A-T (Barlow et al., 1996), and so we attempted to use LPS-induced neuronal damage to mimic the neurological defects in human A-T. Although the reactions to systemic injections are complex, we wished to sort out the role(s) of individual proinflammatory cytokines as mediators of the LPS effect. To do this, we injected wild-type and Atm−/− animals (3 months old) daily with TNFα (70 µg/kg) or IL1β (5 µg/kg) injections for 4 d. As expected, both cytokines triggered the activation of Iba-1-positive microglia in wild-type (Fig. 1A–C) and Atm−/−(Fig. 1D–F) cerebella. When we used GFAP to measure astrocytic activation, however, the cytokines produced evidence of astrogliosis only in Atm-/- but not in wild-type (Fig. 1G–L) cerebella. Although our analysis involved both mutant and wild-type animals, only images from mutants are shown.

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