Melissa Trotman-Lucas, PhD
Lemarchand E, Barrington J, Chenery A, Haley M, Coutts G, Allen JE, et al. Extent of Ischemic Brain Injury After Thrombotic Stroke Is Independent of the NLRP3 (NACHT, LRR and PYD Domains-Containing Protein 3) Inflammasome. Stroke. 2019;50:1232-1239.
Inflammation plays a key role in the fight against infection. However, following ischaemic brain injury, inflammation can play a very different role, exacerbating the severity of damage. Inflammation results in long lasting, ongoing damage from the onset of vessel blockage through to and during reperfusion of the ischaemic brain area. One possible player within the inflammation related post-stroke damage is the NLR family pyrin domain containing 3 (NLRP3) inflammasome. During ischaemic brain injury, NLRP3 senses multiple stroke-induced stimuli leading to the recruitment of the adaptor protein ASC (the apoptosis-associated speck-like pro-caspase-1) resulting in caspase 1 production leading to downstream IL-1β and IL-18 production and release. IL-1β is well-reported to have significant pro-inflammatory and pro-apoptotic effects during acute ischaemic stroke.
A recent study by Lemarchand et al., published in Stroke, sought to determine the importance of NLRP3 to the damage occurring following ischaemic brain damage. Previous studies have reported associations between NLRP3 and an increase in the severity of ischaemic brain injury, leading to the suggestion that targeting NLRP3 could be a potential therapeutic avenue. These previous studies report NLRP3 inhibition to be protective during ischaemia, alongside data showing that mice deficient in NLRP3 show decreased damage when compared to WT counterparts. However, contrary to this, the group responsible for the paper discussed here have previously reported that ischaemic brain injury develops independent of the NLRP3 inflammasome in a rodent model of stroke, suggesting instead that the NLRC4 (NLR family, CARD containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to the resulting brain injury, independent of NLRP3. Lemarchand et al. sought to categorically determine the role of NLRP3 in ischaemic stroke damage, using genetic and pharmacological inhibition of NLRP3. Furthermore, to increase the robustness of the data, the group utilized the FeCl3 (ferric chloride induced thrombosis) model of preclinical ischaemic stroke, where FeCl3 soaked strips are applied to the middle cerebral artery causing localized and immediate thrombus formation, a model that may have considerable clinical relevance.