Blocking Formation of Neurotoxic Reactive Astrocytes is Beneficial Following Stroke.
Kimberly PrescottAlexandra E MünchEvan BrahmsMaya M WeigelKenya InoueMarion S BuckwalterShane A LiddelowTodd C PetersonPublished in: bioRxiv : the preprint server for biology (2023)
Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1α (IL1α), and complement component 1q (C1q), together 'TIC'. This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.
Keyphrases
- atrial fibrillation
- induced apoptosis
- inflammatory response
- neuropathic pain
- oxidative stress
- obsessive compulsive disorder
- end stage renal disease
- cell cycle arrest
- traumatic brain injury
- wild type
- rheumatoid arthritis
- cerebral ischemia
- fatty acid
- chronic kidney disease
- single cell
- ejection fraction
- newly diagnosed
- transcription factor
- heart failure
- acute myocardial infarction
- emergency department
- peritoneal dialysis
- drug induced
- diabetic rats
- cell death
- liver failure
- endoplasmic reticulum stress
- prognostic factors
- patient reported outcomes
- percutaneous coronary intervention
- blood brain barrier
- acute coronary syndrome
- coronary artery disease
- extracorporeal membrane oxygenation
- acute respiratory distress syndrome
- pi k akt
- patient reported