Emerging role of the P2X7-NLRP3-IL1β pathway in mood disorders
Abstract
The science of neuroimmunopsychiatry has evolved rapidly in the last few years with the hope of tackling the unmet need in mood disorders. This article focuses on an inflammatory pathway, highly conserved in myeloid cells that may play a role in neuroinflammatory disorders including depression. Within the brain tissue, microglia are the myeloid cells that express the P2X7 ion channel that is connected through the NLRP3 inflammasome complex leading to release of IL-1β and IL-18. We present, in the way of reviewing relevant literature, the preclinical data and scientific rationale supporting the role of the P2X7-NLRP3-IL-1β pathway in mood disorders. We also highlight recent advances in drug discovery and development of P2X7 small molecule antagonists and P2X7 PET ligands which provide optimism that clinical tools are availableto address critical proof-of-concept experiments in mood disorders.
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Consequently, there is an activation of caspase-1 and maturation of IL-1β and IL-18, resulting in pro-inflammatory cytokine release.
“Consequently, there is an activation of caspase-1 and maturation of IL-1β and IL-18, resulting in pro-inflammatory cytokine release [16, 20, 52, 71, 73].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [73]
Increased ATP levels induced by stress exposure may stimulate P2X7R, leading to diminished intracellular K+ concentration, subsequent NLRP3 inflammasome activation and secretion of pro-inflammatory cytokines.
“Altogether, these data support the notion that increased ATP levels induced by stress exposure may stimulate P2X7R leading to diminished intracellular K+ concentration, with subsequent NLRP3 inflammasome activation and secretion of pro-inflammatory cytokines [93,154].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [154]
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Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology
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- Authors
- Bhattacharya, A., & Jones, D. N. C.
- Affiliations
- Janssen Research & Development (United States) (US)
- Johnson & Johnson (United Kingdom) (GB)
- Corresponding author
- Bhattacharya, Anindya
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 98
- Pages
- 95-100
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2885580638
- Cited by
- 105
- References
- 74
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 10 · 2023: 17 · 2022: 25 · 2021: 12 · 2020: 14 · 2019: 10 · 2018: 1
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- NLRP3 inflammasome, IL-1β, neuroinflammation, mood disorders, depression, microglia, P2X7 antagonists, brain-penetrant drugs, PET ligands, myeloid cells, IL-18
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Depression, Humans, Inflammation, Neuroimmunomodulation, Microglia, Mood Disorders, Myeloid Cells, Interleukin-1beta, Receptors, Purinergic P2X7, Purinergic P2X Receptor Antagonists
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