PPubMed1 Jan 2021Cited 27×

TLR2 and the NLRP3 inflammasome mediate IL-1β production in <i> Prevotella nigrescens </i> -infected dendritic cells

Hye-Mi Jang, Ji-Yeon Park, Yeon-Ji Lee, Min-Jung Kang, Sung-Gang Jo, Yu-Jin Jeong, Nam-Pyo Cho, Sung-Dae Cho, Dong-Jae Kim, Jong-Hwan Park

Abstract

'Yu-Jin Jeong' 'Nam-Pyo Cho' 'Sung-Dae Cho' 'Dong-Jae Kim' 'Jong-Hwan Park'] Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1β (IL-1β) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1β production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1β induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1β into mature IL-1β. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X7R activity, and release of cathepsin B are involved in IL-1β production in BMDCs in response to P. nigrescens.

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TLR2 signaling and the NLRP3 inflammasome are essential for IL-1β production by dendritic cells infected with Prevotella nigrescens.

What’s new

i.Showed that TLR2 provides the priming signal for IL-1β production in P. nigrescens‑infected bone‑marrow‑derived dendritic cells (BMDCs).
ii.Demonstrated that the NLRP3 inflammasome is required for caspase‑1 activation and maturation of IL‑1β in this context.
iii.Identified infection‑induced reactive oxygen species (ROS) as a contributor to NLRP3 activation.
iv.Used a panel of knockout mice (TLR2‑/‑, TLR4‑/‑, NLRP3‑/‑, NLRC4‑/‑, ASC‑/‑, Caspase‑1/11‑/‑) to dissect the signaling pathway.
v.Provided dose‑response data across multiple multiplicities of infection (MOI 1, 10, 100).

How they did it

Bone‑marrow‑derived dendritic cells from wild‑type and various knockout mice were cultured, infected with heat‑killed Prevotella nigrescens at different MOIs, and cytokine levels were measured by ELISA. Immunoblotting assessed caspase‑1 and IL‑1β processing, while real‑time PCR quantified IL‑1β and NLRP3 transcripts. ROS production was visualized using a DCFDA fluorescence assay.

What they found

IL‑1β secretion was markedly reduced in TLR2‑/‑ and NLRP3‑/‑ BMDCs compared with wild‑type cells.
Caspase‑1 activation and mature IL‑1β protein were absent in NLRP3‑/‑ and ASC‑/‑ cells, confirming inflammasome dependence.
ROS generation increased with higher MOI infection, suggesting a role as a second signal for NLRP3 activation.
IL‑6 production was not significantly altered, indicating specificity of the TLR2‑NLRP3 pathway for IL‑1β.

Caveats

✕Experiments used heat‑killed bacteria, which may not fully recapitulate live infection dynamics.
✕All studies were performed in vitro with mouse BMDCs; in vivo relevance remains to be validated.
✕Only one Prevotella strain was examined, limiting generalizability to other oral microbes.
✕The precise molecular link between ROS and NLRP3 activation was not delineated.

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