title: 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-1β (IL-1β). 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-1β expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1β secretion by hematopoietic macrophages, microglial secretion of IL-1β 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.
authors.affiliation: Alternatives Unit.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Burm
authors.affiliation: Alternatives Unit.
authors.forename: Ella A
authors.initials: EA
authors.lastname: Zuiderwijk-Sick
authors.affiliation: Alternatives Unit.
authors.forename: Anke E J
authors.initials: AE
authors.lastname: 't Jong
authors.affiliation: Alternatives Unit.
authors.forename: Céline
authors.initials: C
authors.lastname: van der Putten
authors.affiliation: Alternatives Unit.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Veth
authors.affiliation: Animal Science Department, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands.
authors.forename: Ivanela
authors.initials: I
authors.lastname: Kondova
authors.affiliation: Alternatives Unit, bajramovic@bprc.nl.
authors.forename: Jeffrey J
authors.identifier: http://orcid.org/0000-0002-6504-3437
authors.initials: JJ
authors.lastname: Bajramovic
mesh_terms: D000818:Animals; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D011930:Reaction Time
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D020169:Caspases
keywords: IL-1β; inflammasome; inflammatory caspases; macrophages; microglia