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Adenosine A(2A) receptor mediates microglial process retraction.

Orr AG, Orr AL, Li XJ, Gross RE, Traynelis SF - Nat. Neurosci. (2009)

Bottom Line: Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation.Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling.Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA. anna.orr@gladstone.ucsf.edu

ABSTRACT
Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate and motile cell processes. The motility of these processes is guided by the local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. We identified a molecular pathway in mouse and human microglia that converted ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A(2A) adenosine receptor coincident with P2Y(12) downregulation. Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

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Human microglia exhibit a similar shift in purinergic receptor expression and chemotactic response to ATP(a) Activated human microglia upregulate A2A mRNA and downregulate P2Y12 mRNA (n = 4). (b) Untreated human microglia migrate toward ATP (Control: n = 6, 0.5 mM), while LPS-activated microglia migrate away from ATP (LPS: n = 5).
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Figure 6: Human microglia exhibit a similar shift in purinergic receptor expression and chemotactic response to ATP(a) Activated human microglia upregulate A2A mRNA and downregulate P2Y12 mRNA (n = 4). (b) Untreated human microglia migrate toward ATP (Control: n = 6, 0.5 mM), while LPS-activated microglia migrate away from ATP (LPS: n = 5).

Mentions: Interestingly, A2A receptor upregulation has also been reported in human macrophages and in brain tissue from Alzheimer’s disease patients21,22. Thus, we investigated whether adult human microglia also upregulate A2A expression upon inflammation-driven activation and consequently display chemotactic reversal in response to ATP. We observed that LPS-activated adult human microglia exhibited marked A2A upregulation along with a loss in P2Y12 expression (Fig. 6a). Importantly, while unstimulated human microglia showed migration toward and engulfment of an ATP-filled pipette, LPS-stimulated human microglia exhibited repulsion (Fig. 6b and Supplementary Videos 5 and 6). Thus, a similar chemotactic switch takes place in adult human microglia.


Adenosine A(2A) receptor mediates microglial process retraction.

Orr AG, Orr AL, Li XJ, Gross RE, Traynelis SF - Nat. Neurosci. (2009)

Human microglia exhibit a similar shift in purinergic receptor expression and chemotactic response to ATP(a) Activated human microglia upregulate A2A mRNA and downregulate P2Y12 mRNA (n = 4). (b) Untreated human microglia migrate toward ATP (Control: n = 6, 0.5 mM), while LPS-activated microglia migrate away from ATP (LPS: n = 5).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2712729&req=5

Figure 6: Human microglia exhibit a similar shift in purinergic receptor expression and chemotactic response to ATP(a) Activated human microglia upregulate A2A mRNA and downregulate P2Y12 mRNA (n = 4). (b) Untreated human microglia migrate toward ATP (Control: n = 6, 0.5 mM), while LPS-activated microglia migrate away from ATP (LPS: n = 5).
Mentions: Interestingly, A2A receptor upregulation has also been reported in human macrophages and in brain tissue from Alzheimer’s disease patients21,22. Thus, we investigated whether adult human microglia also upregulate A2A expression upon inflammation-driven activation and consequently display chemotactic reversal in response to ATP. We observed that LPS-activated adult human microglia exhibited marked A2A upregulation along with a loss in P2Y12 expression (Fig. 6a). Importantly, while unstimulated human microglia showed migration toward and engulfment of an ATP-filled pipette, LPS-stimulated human microglia exhibited repulsion (Fig. 6b and Supplementary Videos 5 and 6). Thus, a similar chemotactic switch takes place in adult human microglia.

Bottom Line: Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation.Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling.Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA. anna.orr@gladstone.ucsf.edu

ABSTRACT
Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate and motile cell processes. The motility of these processes is guided by the local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. We identified a molecular pathway in mouse and human microglia that converted ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A(2A) adenosine receptor coincident with P2Y(12) downregulation. Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

Show MeSH
Related in: MedlinePlus