Inflammasome-Induced IL-1β Secretion in Microglia Is Characterized by Delayed Kinetics and Is Only Partially Dependent on Inflammatory Caspases

Abstract

Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1␤ (IL-1␤). Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages and dendritic cells, much less is known about microglia, resident tissue macrophages of the brain that originate from a distinct progenitor. To directly compare inflammasome-mediated activation in different types of macrophages, we isolated primary microglia and hematopoietic macrophages from adult, healthy rhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerization domain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation and regulation in detail. We here demonstrate that primary microglia can respond to the same innate stimuli as hematopoietic macrophages. However, microglial responses are more persistent due to lack of negative regulation on pro-IL-1␤ expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1␤ secretion by hematopoietic macrophages, microglial secretion of IL-1␤ is only partially dependent on these inflammatory caspases. These results identify key cell type-specific differences that may aid the development of strategies to modulate innate immune responses in the brain.

Edaravone Attenuates the Proinflammatory Response in Amyloid-β-Treated Microglia by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion

“…Therefore, microglia were primed with 500 ng/ml LPS for 4 h and then exposed to different treatments. Consistent with the results from other studies [32,33], IL-1β was detected in culture supernatants from LPS-primed microglia. LPS-primed microglia were untreated or incubated with Aβ (1-10 μM) for 24 h. As shown in Fig.…”

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

“…In a recent study, priming of primate primary microglia with varying concentrations (4-500ng/ml) of LPS resulted in similar amount of IL-1β release at least at the 4h time point (Burm et al, 2015). Therefore, experiments were performed at a similar time point with primary microglia.…”

“…There are a plethora of studies that demonstrates NLRP3 activation in bone-marrow derived macrophages and dendritic cells (Burm et al, 2015); however, only scant evidence are available regarding the mechanisms regulating the priming and activation of NLRP3 inflammasome in the microglia (Gustin et al, 2015). In the present study, we investigated the inflammatory mechanisms involved in ROT-stimulated LPS-primed microglia using BV2 microglial cell line and mouse primary microglia.…”

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

“…Further, inflammasome-dependent activation of IL-1β is cell type specific (Netea et al, 2015). Interestingly, Burm et al (2015) have recently demonstrated that IL-1β activation is not strictly caspase-1 dependent in primary microglia, suggesting that inflammasomes may not be necessary for the processing of IL-1β into its mature form in this CNS innate immune cell. These are important points to consider in studies that examine the role of brain inflammasomes in animal models of depression.…”