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Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling

Jiezhou Ye1, Bo Zeng1, Meiyan Zhong1

  • 1Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.

Acta Pharmaceutica Sinica. B
|February 3, 2021
PubMed

Insights

Scutellarin, a flavonoid, inhibits caspase-11 activation and pyroptosis in macrophages. This natural compound regulates the protein kinase A (PKA) signaling pathway, offering potential therapeutic benefits for inflammatory diseases.

Area of Science:

  • Immunology
  • Pharmacology
  • Cell Biology

Background:

  • Caspase-11 activation by intracellular lipopolysaccharide (LPS) triggers pyroptosis, crucial for bacterial defense but implicated in inflammatory diseases.
  • Limited therapeutic agents exist to control excessive caspase-11 activation.
  • Scutellarin, a flavonoid from Erigeron breviscapus, is investigated for its inhibitory effects on caspase-11.

Purpose of the Study:

  • To investigate scutellarin's inhibitory effects on caspase-11 activation and pyroptosis in macrophages.
  • To elucidate the molecular mechanisms underlying scutellarin's action, including its impact on inflammasome pathways and signaling cascades.

Main Methods:

  • Assessed scutellarin's effect on LPS-induced caspase-11 activation, pyroptosis, and gasdermin D (GSDMD) cleavage in macrophages.
  • Evaluated scutellarin's impact on the non-canonical NLRP3 inflammasome pathway, including ASC speck formation and cytokine secretion.
  • Investigated scutellarin's influence on caspase-11 phosphorylation and its interaction with the protein kinase A (PKA) signaling pathway.

Main Results:

  • Scutellarin dose-dependently inhibited LPS-induced caspase-11 activation and pyroptosis, evidenced by reduced caspase-11p26 and GSDMD-NT generation.
  • Scutellarin suppressed NLRP3 inflammasome activation, indicated by decreased ASC speck formation and IL-1β/caspase-1 secretion, independently of ASC expression.
  • Scutellarin treatment enhanced caspase-11 phosphorylation at PKA-specific sites, and its inhibitory effects were reversed by PKA and adenylyl cyclase inhibitors.

Conclusions:

  • Scutellarin effectively inhibits caspase-11 activation and subsequent pyroptosis in macrophages.
  • The mechanism involves, at least partly, the modulation of the PKA signaling pathway.
  • Scutellarin represents a potential therapeutic candidate for controlling inflammatory conditions driven by caspase-11 overactivation.
Keywords:
Caspase-11Gasdermin DMacrophagesPKA signalingPyroptosisScutellarin

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