1. Academic Validation
  2. MTOR Suppresses Environmental Particle-Induced Inflammatory Response in Macrophages

MTOR Suppresses Environmental Particle-Induced Inflammatory Response in Macrophages

  • J Immunol. 2018 Apr 15;200(8):2826-2834. doi: 10.4049/jimmunol.1701471.
Zhouyang Li 1 Yinfang Wu 1 Hai-Pin Chen 1 Chen Zhu 1 Lingling Dong 1 Yong Wang 1 Huiwen Liu 1 Xuchen Xu 1 Jiesen Zhou 1 Yanping Wu 1 Wen Li 1 Songmin Ying 1 Huahao Shen 2 3 Zhi-Hua Chen 2
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; and.
  • 2 Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; and zhihuachen@zju.edu.cn huahaoshen@zju.edu.cn.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou 510120, China.
Abstract

Increasing toxicological and epidemiological studies have demonstrated that ambient particulate matter (PM) could cause adverse health effects including inflammation in the lung. Alveolar macrophages represent a major type of innate immune responses to foreign substances. However, the detailed mechanisms of inflammatory responses induced by PM exposure in macrophages are still unclear. We observed that coarse PM treatment rapidly activated mechanistic target of rapamycin (mTOR) in mouse alveolar macrophages in vivo, and in cultured mouse bone marrow-derived macrophages, mouse peritoneal macrophages, and RAW264.7 cells. Pharmacological inhibition or genetic knockdown of mTOR in bone marrow-derived macrophages leads to an amplified cytokine production upon PM exposure, and mice with specific knockdown of mTOR or Ras homolog enriched in brain in myeloid cells exhibit significantly aggregated airway inflammation. Mechanistically, PM activated mTOR through modulation of ERK, Akt serine/threonine kinase 1, and tuberous sclerosis complex signals, whereas mTOR deficiency further enhanced the PM-induced Necroptosis and activation of subsequent NF κ light-chain-enhancer of activated B cells (NFKB) signaling. Inhibition of Necroptosis or NFKB pathways significantly ameliorated PM-induced inflammatory response in MTOR-deficient macrophages. The present study thus demonstrates that mTOR serves as an early adaptive signal that suppresses the PM-induced Necroptosis, NFKB activation, and inflammatory response in lung macrophages, and suggests that activation of mTOR or inhibition of Necroptosis in macrophages may represent novel therapeutic strategies for PM-related airway disorders.

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