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Genetic inactivation of the adenosine A(2A) receptor exacerbates brain damage in mice with experimental autoimmune
Shu-Qin Yao1, Zheng-Zheng Li, Qing-Yuan Huang
1Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, PR China.
Abstract:
Studies with multiple sclerosis patients and animal models of experimental autoimmune encephalomyelitis (EAE) implicate adenosine and adenosine receptors in modulation of neuroinflammation and brain injury. Although the involvement of the A(1) receptor has been recently demonstrated, the role of the adenosine A(2A) receptor (A(2A)R) in development of EAE pathology is largely unknown. Using mice with genetic inactivation of the A(2A) receptor, we provide direct evidence that loss of the A(2A)R exacerbates EAE pathology in mice. Compared with wild-type mice, A(2A)R knockout mice injected with myelin oligodendroglia glycoprotein peptide had a higher incidence of EAE and exhibited higher neurological deficit scores and greater decrease in body weight. A(2A)R knockout mice displayed increased inflammatory cell infiltration and enhanced microglial cell activation in cortex, brainstem, and spinal cord. In addition, demyelination and axonal damage in brainstem were exacerbated, levels of Th1 cytokines increased, and Th2 cytokines decreased. Collectively, these findings suggest that extracellular adenosine acting at A(2A)Rs triggers an important neuroprotective mechanism. Thus, the A(2A) receptor is a potential target for therapeutic approaches to multiple sclerosis.
Insights
Loss of the adenosine A(2A) receptor (A(2A)R) worsens experimental autoimmune encephalomyelitis (EAE) pathology in mice. This suggests A(2A)R activation is neuroprotective and a potential therapeutic target for multiple sclerosis.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Adenosine and its receptors modulate neuroinflammation and brain injury in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
- The role of the adenosine A(2A) receptor (A(2A)R) in EAE pathogenesis remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of the adenosine A(2A) receptor (A(2A)R) in the development of EAE pathology.
- To determine if A(2A)R signaling confers neuroprotection in EAE.
Main Methods:
- Utilized genetically modified mice lacking functional A(2A)R (A(2A)R knockout).
- Induced EAE in knockout and wild-type mice using myelin oligodendrocyte glycoprotein peptide.
- Assessed EAE incidence, neurological deficit scores, body weight changes, inflammatory cell infiltration, microglial activation, demyelination, axonal damage, and cytokine profiles (Th1/Th2).
Main Results:
- A(2A)R knockout mice exhibited a higher incidence of EAE, increased neurological deficits, and significant body weight loss compared to wild-type controls.
- Enhanced inflammatory cell infiltration and microglial activation were observed in the central nervous system of knockout mice.
- Exacerbated demyelination and axonal damage, along with increased Th1 and decreased Th2 cytokine levels, were noted in A(2A)R knockout mice.
Conclusions:
- Loss of A(2A)R function exacerbates EAE pathology, indicating a crucial neuroprotective role for A(2A)R signaling.
- Extracellular adenosine acting via A(2A)Rs initiates a significant neuroprotective mechanism.
- The adenosine A(2A) receptor represents a promising therapeutic target for managing multiple sclerosis.
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