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

Xueyu Geng1,2, Xue Xia3, Zhenhui Liang1,2

  • 1Hemorheology Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Cellular and Molecular Life Sciences : CMLS
|September 14, 2024
PubMed

Insights

Tropomodulin 1 (Tmod1) hinders Toll-like receptor 4 (TLR4) endocytosis in macrophages, impacting inflammatory responses. Tmod1 deficiency alleviates inflammation in sepsis models, suggesting Tmod1 as a therapeutic target.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Sepsis results from excessive inflammation due to prolonged Toll-like receptor 4 (TLR4) activation.
  • CD14-mediated endocytosis of TLR4 regulates cell surface levels and downstream signaling, but the role of the actin cytoskeleton is unclear.
  • Tropomodulin 1 (Tmod1), an actin capping protein, is investigated for its role in TLR4 endocytosis.

Purpose of the Study:

  • To elucidate the role of Tropomodulin 1 (Tmod1) in regulating Toll-like receptor 4 (TLR4) endocytosis and inflammatory signaling in macrophages.
  • To investigate the potential of Tmod1 as a therapeutic target for sepsis and excessive inflammation.

Main Methods:

  • Investigated the effect of Tmod1 on lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages.
  • Analyzed the impact of Tmod1 on myeloid differentiation factor 88 (MyD88)-dependent and TIR domain-containing adaptor-inducing interferon-β (TRIF)-dependent pathways.
  • Assessed inflammatory cytokine secretion (TNF-α, IL-6, IFN-β) and evaluated Tmod1-deficient macrophages in an LPS-induced acute lung injury mouse model.

Main Results:

  • Tmod1 inhibited LPS-induced TLR4 endocytosis and intracellular trafficking, leading to increased surface TLR4.
  • Tmod1 modulated MyD88 and TRIF pathway activity, enhancing pro-inflammatory cytokine (TNF-α, IL-6) and reducing anti-inflammatory cytokine (IFN-β) secretion.
  • Tmod1 deficiency in macrophages ameliorated inflammatory responses in an acute lung injury mouse model.

Conclusions:

  • Tmod1 negatively regulates TLR4 endocytosis and inflammatory responses by modulating CD14/Syk/PLCγ2/IP3/Ca2+ signaling, actin cytoskeleton reorganization, and membrane tension.
  • Tmod1 is a key regulator of macrophage immune function and inflammatory responses.
  • Tmod1 represents a potential therapeutic target for treating excessive inflammation and sepsis.
Keywords:
Cytoskeletal proteinEndocyosisInflammatory responseMacrophageToll-like receptor 4

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