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Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response

Songqing Tang1,2, Taoyong Chen2, Mingjin Yang2,3

  • 1Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.

Cellular & Molecular Immunology
|August 18, 2015
PubMed

Insights

Extracellular calcium enhances macrophage activation via Toll-like receptor (TLR) signaling feedforward regulation. This calcium influx, mediated by STIM1, coordinates small GTPases Ras and Rap1 for appropriate innate immune responses to microbes.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Toll-like receptor (TLR) signaling is crucial for innate immunity against microbial invaders.
  • While feedback mechanisms are well-studied, feedforward regulation of TLR signaling remains less understood.
  • Understanding these pathways is key to developing effective immune therapies.

Purpose of the Study:

  • To investigate the role of extracellular calcium in the feedforward regulation of TLR signaling.
  • To elucidate the mechanisms by which calcium influences macrophage activation and innate immune responses.
  • To identify key molecular players involved in calcium-mediated TLR signal potentiation.

Main Methods:

  • Utilized TLR agonists to stimulate macrophages and measured cytokine production.
  • Assessed the impact of extracellular calcium levels using calcium chelators (EGTA) and STIM1 knockdown.
  • Analyzed the activation status of small GTPases Ras and Rap1 using biochemical assays.
  • Investigated downstream signaling pathways, including extracellular signal-regulated kinase (ERK).

Main Results:

  • Extracellular calcium potentiates TLR-triggered cytokine production in macrophages.
  • Calcium depletion (EGTA) or STIM1 knockdown impairs TLR-induced innate immune responses.
  • TLR stimulation alters the balance of GTP-bound Ras (increased) and Rap1 (decreased), which is calcium-dependent.
  • Rap1 knockdown rescues the inhibitory effects of calcium depletion on TLR responses.
  • Extracellular calcium regulates the TLR response via feedforward activation of the ERK pathway.

Conclusions:

  • Extracellular calcium plays a critical role in the feedforward regulation of TLR signaling.
  • Calcium influx, potentially mediated by STIM1-operated channels, integrates TLR stimulus intensity.
  • This mechanism ensures appropriate levels of innate immune activation in response to microbial challenges.
  • The findings provide mechanistic insights into TLR-triggered innate immune responses.

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