Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke

Abstract

Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen–glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1β and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1β and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

“…As mentioned above, several studies have evaluated the contribution of inflammasome forming NLRs in TBI in both human and rodent models (6–9, 45). However, data pertaining to non-inflammasome forming regulatory NLR family members has yet to be evaluated.…”

“…Beyond neurodegenerative diseases, inflammasome forming NLRs have also been found to significantly modulate various pathologic features of both traumatic and non-traumatic brain injury. Of the inflammasome forming NLRs in brain injury, the NLRP1 and NLRP3 inflammasomes are the best characterized in mice and the majority of studies have focused on mechanisms associated with regulating IL-1β/IL-18 and pyroptosis (6–8, 45, 50). However, aside from the inflammasome, there is a paucity of data pertaining to the role of non-inflammasome forming regulatory NLRs in brain injury.…”

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

“…Further, the importance of posttranscriptional regulation of inflammasome components is described to be relevant for the fine-tuning of inflammasome action. Inflammasome components such as NLRP1/NLRP3 and IL1β/IL18 are increased in neural cells under experimental hypoxia and in stroke patients [43,46]. NLRP1 plays a crucial role in damaged neurons since NLRP1-specific antibodies reduced inflammatory cytokine levels and were neuroprotective [43].…”

The role of inflammasome in Alzheimer's disease

“…IL-1β and IL-18. Inflammasomes involve in the maturation of IL-1β and IL-18 are expressed in neurons (de Rivero Vaccari et al, 2008; Yang-Wei Fann et al, 2013; Zou and Crews, 2012). Trauma, a risk factor for AD, increases inflammasome expression in rat neurons (de Rivero Vaccari et al, 2009; de Rivero Vaccari et al, 2008).…”