Extracellular mitochondrial DNA promote NLRP3 inflammasome activation and induce acute lung injury through TLR9 and NF-κB

Abstract

Background: Extracellular mitochondrial DNA (mtDNA) was demonstrated to be capable of inducing pulmonary inflammation through TLR9 while its role in NLRP3 inflammation activation remains unknown.Methods: C57BL/6 mice were challenged intratracheally with mtDNA. Pulmonary pathology, the NLRP3 and caspase-1 p20 in lung tissues were assayed. PMA-primed THP-1 macrophages were incubated with mtDNA in vitro and cell-free medium were concentrated to detect caspase-1 p20 subunit and NLRP3 by Western blotting. Additionally, IL-1β, L-18, TNF-α and caspase-1 activity in culture were also analyzed by ELISA kits and activity assay kit. Results: Intratracheal administration of mtDNA increased NLRP3 and caspase-1 p20 subunit in lung together with excessive inflammation and damage. Inhibition of caspase-1 substantially diminished mtDNAinduced lung injury and inflammation. Exposed to mtDNA in THP-1 macrophages resulted in significant up-regulation of NLRP3 and increased caspase-1 p20 subunit release in culture. It also led to significant increased transcripts of NLRP3, ASC, caspase-1 and release of IL-1β, IL-18 and TNF-α in culture media. Futhermore, mtDNA exposure resulted in significant up-regulation of phosho -p38 MAPK and nucleus translocation of NF-κB. mtDNA-induced Transcripts of NLRP3 and ASC were inhibited by p38 siRNA inhibitor or NF-κB inhibitor. Conclusions: Extracellular mtDNA promote NLRP3 inflammasome activation, acute pulmonary inflammation and injury through TLR9, p38 MAPK and NF-κB pathways.

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“…Following trauma, numerous mediators known as DAMPs are immediately released into circulation 26 . The “alarmins” DAMPs may be nuclear or cytosolic proteins, extracellular matrix, or metabolic products 27–44 (Table 2). Plasma levels of DAPMs are associated with cellular immunity impairment in trauma patients 45 .…”

“…Toll‐like receptors (TLRs) are the main PRR for detection of DAMPs and TLR activation could predict the pathological conditions in trauma patients 48,49 . An important inflammatory signal TLR‐MyD88 was activated by DAPMs triggered a cascade signal response that increase the transcription activity of nuclear factor kappa‐B (NF‐κB) 44 …”

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“…Initially, viral components (capsid, nucleic acids) are detected by intracellular receptors (PRRs) that activate proinflammatory responses ( Sparrer and Gack, 2015 ; Lee et al, 2019 ; Matz et al, 2019 ). Mitochondria regulate viral detection and subsequent immune responses through the activation of the MAVS protein ( Vazquez et al, 2015 ), the release of mtDNA ( Wu et al, 2019 ; Riley and Tait, 2020 ), or through MAM modulation ( Reshi et al, 2018 ). MAVS activation is a key event following infection with RNA viruses.…”

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