2. Academic Validation
  3. Tropomodulin1 exacerbates inflammatory response in macrophages by negatively regulating LPS-induced TLR4 endocytosis

Tropomodulin1 exacerbates inflammatory response in macrophages by negatively regulating LPS-induced TLR4 endocytosis

  • Cell Mol Life Sci. 2024 Sep 14;81(1):402. doi: 10.1007/s00018-024-05424-8.
Xueyu Geng 1 2,  Xue Xia 3,  Zhenhui Liang 1 2,  Shuo Li 1,  Zejun Yue 1 2,  Huan Zhang 1,  Lina Guo 4,  Shan Ma 5,  Siyu Jiang 5,  Xiang Lian 6,  Jing Zhou 1,  Lanping Amy Sung 7,  Xifu Wang 8,  Weijuan Yao 9 10
Affiliations

Affiliations

  • 1 Hemorheology Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 2 Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University Health Center, Beijing, 100191, China.
  • 3 Nanjing Institute of Measurement and Testing Technology, Nanjing, 210049, Jiangsu Province, China.
  • 4 Department of Rehabilitation Medicine, Caoxian People's Hospital, Heze, 274400, Shandong Province, China.
  • 5 Chengde Medical College, Chengde, 067000, Hebei Province, China.
  • 6 Department of Emergency, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
  • 7 Department of Bioengineering, University of California, La Jolla, San Diego, CA, 92093, USA.
  • 8 Department of Emergency, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. wxf0439@163.com.
  • 9 Hemorheology Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. weijuanyao@bjmu.edu.cn.
  • 10 Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University Health Center, Beijing, 100191, China. weijuanyao@bjmu.edu.cn.
PMID: 39276234 DOI: 10.1007/s00018-024-05424-8
Abstract

The excessive inflammation caused by the prolonged activation of Toll-like Receptor 4 (TLR4) and its downstream signaling pathways leads to sepsis. CD14-mediated endocytosis of TLR4 is the key step to control the amount of TLR4 on cell membrane and the activity of downstream pathways. The actin Cytoskeleton is necessary for receptor-mediated endocytosis, but its role in TLR4 endocytosis remains elusive. Here we show that Tropomodulin 1 (Tmod1), an actin capping protein, inhibited lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages. Thus it resulted in increased surface TLR4 and the upregulation of myeloid differentiation factor 88 (MyD88)-dependent pathway and the downregulation of TIR domain-containing adaptor-inducing interferon-β (TRIF)-dependent pathway, leading to the enhanced secretion of inflammatory cytokines, such as TNF-α and IL-6, and the reduced secretion of cytokines, such as IFN-β. Macrophages deficient with Tmod1 relieved the inflammatory response in LPS-induced acute lung injury mouse model. Mechanistically, Tmod1 negatively regulated LPS-induced TLR4 endocytosis and inflammatory response through modulating the activity of CD14/Syk/PLCγ2/IP3/CA2+ signaling pathway, the reorganization of actin Cytoskeleton, and the membrane tension. Therefore, Tmod1 is a key regulator of inflammatory response and immune functions in macrophages and may be a potential target for the treatment of excessive inflammation and sepsis.

Keywords

Cytoskeletal protein; Endocyosis; Inflammatory response; Macrophage; Toll-like receptor 4.

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