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The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory

Zhi Chen1, Wei-Hua Dong2, Zhong-Min Qiu3

  • 1Department of Critical Care Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, Jiangxi, China; Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.

Molecular Therapy. Nucleic Acids
|September 1, 2020
PubMed

Insights

Monocyte exosomes carrying CLMAT3 long noncoding RNA promote inflammation in acute lung injury by activating the CtBP2-p300-NF-κB pathway. Inhibiting CtBP2 reduces this inflammatory response.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Monocytes and macrophages are key innate immune cells.
  • Exosomes mediate cell-to-cell communication via released molecules like long noncoding RNAs (lncRNAs).
  • The role of monocyte-derived exosomes in monocyte-macrophage communication, particularly in acute lung injury (ALI), remains unclear.

Purpose of the Study:

  • To investigate the role of monocyte-derived exosomes in ALI pathogenesis.
  • To identify specific lncRNAs involved in monocyte-macrophage communication during ALI.
  • To elucidate the signaling pathway regulated by CLMAT3 in ALI.

Main Methods:

  • Differential lncRNA profiling in monocytes from healthy controls and ALI patients.
  • Analysis of CLMAT3 targeting and repression of CtBP2 (C-terminal binding protein 2).
  • Investigation of CtBP2's role in forming a transcriptional complex with p300 and NF-κB (nuclear factor κB).
  • In vitro coculture and in vivo studies using ALI monocyte-derived exosomes.
  • Assessment of CtBP2 inhibitors (NSC95397, MTOB) on cytokine production.

Main Results:

  • CLMAT3 was identified as a key lncRNA in ALI monocytes.
  • CLMAT3 was found to specifically target and repress CtBP2 expression.
  • Elevated CtBP2 coactivated the CtBP2-p300-NF-κB complex, inducing proinflammatory cytokines.
  • ALI monocyte-derived exosomes increased proinflammatory cytokine production.
  • CtBP2 inhibitors reversed CtBP2-mediated transactivation and reduced cytokine production.

Conclusions:

  • Monocyte-derived exosomes carrying CLMAT3 contribute to ALI pathogenesis.
  • The CLMAT3-CtBP2-p300-NF-κB axis is a critical pathway for inducing inflammation in ALI.
  • Targeting CtBP2 may offer a therapeutic strategy for ALI.
Keywords:
CLMAT3CtBP2NF-κBacute lung injuryexosomeinflammationp300transactivation

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