The role of inflammasome activation in post-stroke regeneration and recovery

Zhu, Jie (2026): The role of inflammasome activation in post-stroke regeneration and recovery. Dissertation, LMU München: Medizinische Fakultät

Abstract

The WHO identifies stroke as the second most significant cause of global mortality, resulting in roughly 6 million deaths per year and significantly contributing to long-term impairment. A stroke occurs when cerebral blood flow is disrupted, either by the blockage of a cerebral artery or by hemorrhage from a ruptured blood vessel. The following pathophysiological processes are activated, with neuroinflammation significantly influencing the outcomes after a stroke. Following an acute stroke, secondary neuroinflammation is initiated by pro-inflammatory signals released from dying cells in the infarct core area. While this inflammation can exacerbate further injury and lead to cell death, it also plays a beneficial role in promoting tissue repair and recovery. In these processes, the inflammatory response is fundamentally triggered through the crucial inflammasome pathway. The inflammasome is a high-molecular-weight multi-protein complex responsible for initiating the inflammatory response. It consists of a pattern recognition receptor, an adaptor protein and an effector protease caspase-1. The inflammasome becomes activated when the sensor detects pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Upon detecting these signals, pattern recognition receptors (PRRs) bind to the adaptor protein via homotypic protein interactions, leading to the recruitment of pro-caspase-1. This process results in the autocatalytic activation of pro-caspase-1, which primarily functions to proteolytically activate pro-inflammatory cytokines such as interleukin (IL)-1α, IL-β, and IL-18, and to cleave Gasdermin D (GSDMD). This cytosolic protein then triggers a type of programmed cell death known as pyroptosis. Inhibiting inflammasome activation during the acute phase of a stroke has been shown to improve outcomes. At the same time, its activation has also been linked to post-stroke cognitive impairment in the chronic phase. However, the mechanisms underlying post-stroke inflammasome activation and its role in functional recovery remain unclear. This study investigates the spatiotemporal activation of inflammasomes in the post-stroke mouse brain and explores their impact on neuroinflammation and functional recovery. My findings indicate that inflammasome activation differs among various stroke models. In a severe transient middle cerebral artery occlusion model, the activation of the inflammasome persisted into the chronic phase. In contrast, in a moderate photothrombotic (PT) occlusion model, inflammasome activation occurred rapidly but was primarily confined to the acute phase. In the chronic phase following middle cerebral artery occlusion, inflammasome activation was observed in the cortex, striatum, and hippocampus. Notably, the peri-infarct cortex shows prominent activation but minimal activation in the core lesion. Cell-specific contributions to inflammasome activation were also examined. Microglia were primarily involved in inflammasome activation during the subacute to chronic phase (1 to 2 weeks), whereas macrophages and monocytes exhibited greater activity during the acute and subacute phases. Neutrophils exhibited sustained activation from the acute to the chronic phase. Additionally, our findings indicate that acute neuroinflammation following stroke is mainly dependent on inflammasome activity. Caspase-1 deficiency significantly reduced the immune cell infiltration into the brain during both the acute and subacute phases. However, it did not impact the secondary chronic inflammation, which is marked by the aggregation of T and B cells. Furthermore, the role of inflammasome activation in the process of post-stroke regeneration and functional recovery was thoroughly examined. Compared to wild-type (WT) mice, Caspase-1 knockout mice, which lack critical components of the inflammasome pathway, exhibited a reduced post-synaptic density within the peri-infarct cortical region four weeks after stroke, while showing no effect on the colocalized synapses. Additionally, behavioral tests demonstrated delayed functional recovery in inflammasome-deficient mice, underscoring the critical role of the inflammasome in post-stroke rehabilitation processes (Fig. 1). In conclusion, this study presents compelling evidence indicating that inflammasome activation positively influences post-stroke pathology. Our findings suggest that the timing of inflammasome activation may be a critical factor in determining stroke outcomes, highlighting the importance of targeting inflammasome activation within an optimal time window to achieve the best therapeutic results.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: stroke, inflammasome, regeneration, recovery
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 23. Februar 2026
• 1. Bericht­erstatter:in: Liesz, Arthur