NLRP12-PANオプトソームは,ヘムとPAMPに対する反応としてPANオプトーシスと病理を活性化します

Balamurugan Sundaram¹, Nagakannan Pandian¹, Raghvendra Mall¹

¹Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Cell

|June 2, 2023

まとめ

NLRP12は,細胞死亡と炎症につながる炎症体とPANoptosomeの活性化を誘発する細胞センサーです. NLRP12に保護されたマウスを削除し,血解性疾患におけるその役割を強調した.

科学分野:

免疫学
細胞生物学
分子医学

背景:

インフラマソームとPANオプトソームを含む細胞性先天性免疫センサーは,宿主防御と炎症性細胞死亡に不可欠です.
病気におけるNLRP12センサーのトリガーと役割はほとんど不明です.
NLRP12は様々な感染性および炎症性疾患に関与しています.

研究の目的:

NLRP12の活性化トリガーを明らかにする.
NLRP12の炎症体とPANオプトソームの活性化における役割を定義する.
細胞死,炎症,病理学へのNLRP12の寄与を調査する.

主な方法:

ヘムと病原体関連分子パターン (PAMPs) またはTNFによるNLRP12活性化が研究されました.
TLR2/4およびIRF1誘導を含む,トール型受容体 (TLR) 信号伝達経路を利用した.
インフラマソームとPANオプトソーム複合体の形成,シトキンの成熟 (IL-1β,IL-18) と細胞死経路 (カスパース-8/RIPK3) を調べました.
血液溶解性急性腎損傷のマウスモデルを用いてNLRP12のインビヴォの役割を評価した.

主要な成果:

NLRP12は,ヘムとPAMPまたはTNFへの反応として,炎症体とPANオプトソームの活性化を誘導するセンサーとして特定されました.
TLR2/4シグナリングはIRF1を誘発し,Nlrp12の発現を向上させ,炎症ゾームの組み立てを開始した.
インフラマソームはより大きなNLRP12-PANオプトソーム複合体の一部であり,カスパース-8/RIPK3による炎症性細胞死を媒介した.
Nlrp12の削除は,急性腎臓損傷と致死性に対する保護を与えました.

結論:

NLRP12は,ヘムとPAMPが誘発するPANOPTOSIS,炎症,および病理学の重要な細胞センサーとして作用します.
NLRP12は炎症体活性化とより大きなPANOPTOSOME複合体の両方をオーケストラします.
NLRP12とその関連経路分子は,血解性および炎症性疾患の潜在的治療標的を表しています.

キーワード:

DAMP について IRF1 について NLRP12 について PAMP について RIPK3 について TLR2 について TLR4 についてアポトーシスカスパースカスパース-1 カスパース-8 ガスダーミンヘムヘモリシス炎症ゾーム炎症性細胞死ネクロプトーシスピロプトーシス

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