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Study · Animal study (in vivo) · mouse · 2023

1 result

TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury.

Zhong WJ, Zhang J, Duan JX, Zhang CY, Ma SC, Li YS, Yang NS, Yang HH, Xiong JB, Guan CX, Jiang ZX, You ZJ, Zhou Y

Journal of translational medicine6 Mar 2023Cited by 64 (Europe PMC)

PMID36879273 (opens in a new tab)PMCIDPMC9990355 (opens in a new tab)DOI10.1186/s12967-023-04027-4 (opens in a new tab)PepBankPUB-36879273
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Summary

BackgroundNecroptosis of macrophages is a necessary element in reinforcing intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that sparks macrophage necroptosis is still unclear. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor expressed broadly on monocytes/macrophages. The influence of TREM-1 on the destiny of macrophages in ALI requires further investigation.MethodsTREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice. Then we used an agonist anti-TREM-1 Ab (Mab1187) to activate TREM-1 in vitro. Macrophages were treated with GSK872 (a RIPK3 inhibitor), Mdivi-1 (a DRP1 inhibitor), or Rapamycin (an mTOR inhibitor) to investigate whether TREM-1 could induce necroptosis in macrophages, and the mechanism of this process.ResultsWe first observed that the blockade of TREM-1 attenuated alveolar macrophage (AlvMs) necroptosis in mice with LPS-induced ALI. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. We discovered that mTOR had a previously unrecognized function in modulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1Ser616 phosphorylation through mTOR signaling, which in turn caused surplus mitochondrial fission-mediated necroptosis of macrophages, consequently exacerbating ALI.ConclusionIn this study, we reported that TREM-1 acted as a necroptotic stimulus of AlvMs, fueling inflammation and aggravating ALI. We also provided compelling evidence suggesting that mTOR-dependent mitochondrial fission is the underpinning of TREM-1-triggered necroptosis and inflammation. Therefore, regulation of necroptosis by targeting TREM-1 may provide a new therapeutic target for ALI in the future.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Mechanism

    In mice with LPS-induced acute lung injury, TREM-1 blockade with LR12 attenuated alveolar macrophage necroptosis.

    In plain wordsIn mice with LPS-induced lung injury, LR12 reduced inflammatory cell death in alveolar macrophages.

    Peptide
    Nangibotide
    Outcome
    DecreaseAlveolar macrophage necroptosis
    Study

    mousen: not reported in source

    LPS-induced acute lung injury
    Outcome group
    Immune response · Respiratory
    Studied dose
    Dose not stated

    Source sentences

    Summary
    We first observed that the blockade of TREM-1 attenuated alveolar macrophage (AlvMs) necroptosis in mice with LPS-induced ALI.
    1 context sentence
    Summary · context
    TREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice.

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Version history

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  1. Version 2Current

    27 Oct 2026, 18:20 UTC

    Study results updated

  2. Version 1

    27 Oct 2026, 16:32 UTC

    First added · source update from Europe PMC

Subjects

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