Abstract
Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.
Highlights
IL-1b is a potent cytokine that acts on different cell types to induce a proinflammatory response [1], the production of active IL-1b is tightly regulated
Human monocytes were pre-incubated overnight with IFNb or medium, LPS was added to induce the production of pro-IL-1b and the NLRP3 inflammasome was activated by addition of ATP
The secretion of IL-1b is tightly controlled by inflammasomes, multi-protein complexes composed of Nucleotide oligomerization domain receptors (NLRs) and adaptor proteins that aggregate upon exposure to specific activators
Summary
IL-1b is a potent cytokine that acts on different cell types to induce a proinflammatory response [1], the production of active IL-1b is tightly regulated. Familial autoinflammatory syndromes, such as Muckle-Wells-Syndrome, are linked to excessive secretion of IL-1b and have helped to elucidate the mechanisms that regulate the secretion of active IL-1b [2]. Nucleotide oligomerization domain receptors (NLRs) are central components in the majority of inflammasomes, which are complexed with other proteins to form active inflammasomes in response to a plethora of exogenous and endogenous ligands such as ATP, alum or monosodium urate (MSU) crystals [5]. The inflammasomes catalyze the proteolytic maturation of caspase-1, which cleaves pro-IL-1b to IL-1b [3,6]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.