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MKK3 mediates inflammatory response through modulation of mitochondrial function

Anup Srivastava1, Amanda S Shinn1, Patty J Lee1

  • 1Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8057, USA.

Free Radical Biology & Medicine
|February 21, 2015
PubMed

Insights

MAP kinase kinase 3 (MKK3) deficiency improves mitochondrial function and reduces inflammatory responses. MKK3 regulates cytokine secretion, reactive oxygen species, and inflammasome activation, suggesting it as a therapeutic target for inflammatory diseases.

Area of Science:

  • Mitochondrial biology
  • Immunology
  • Cell signaling

Background:

  • Mitochondria are key regulators of inflammatory responses.
  • MAP kinase kinase 3 (MKK3) is activated during inflammation and modulates p38 MAP kinase signaling.
  • MKK3's role in mitochondrial function and inflammation is not fully understood.

Purpose of the Study:

  • To investigate the role of MKK3 in regulating mitochondrial function and inflammatory responses.
  • To determine if MKK3 influences cytokine production, reactive oxygen species generation, and inflammasome activation.
  • To explore MKK3 as a potential therapeutic target for inflammatory disorders.

Main Methods:

  • Utilized MKK3-deficient (MKK3(-/-)) mice and bone marrow-derived macrophages (BMDMs).
  • Assessed mitochondrial function through oxygen consumption, membrane potential, and ATP production.
  • Measured cytokine secretion, reactive oxygen species (ROS), mitochondrial superoxide, NF-κB translocation, and caspase-1 activity.
  • Employed siRNA to knockdown MKK3 in wild-type BMDMs.

Main Results:

  • MKK3(-/-) BMDMs exhibited improved mitochondrial function (basal oxygen consumption, membrane potential, ATP production) compared to wild type (WT).
  • MKK3 deficiency significantly reduced cytokine secretion, cellular ROS production, mitochondrial superoxide, NF-κB nuclear translocation, and caspase-1 activity following lipopolysaccharide (LPS) exposure.
  • Knockdown of MKK3 in WT BMDMs recapitulated these findings, improving mitochondrial membrane potential and reducing inflammation markers.
  • Activation of p38 and JNK signaling pathways was diminished in MKK3(-/-) BMDMs after LPS challenge.

Conclusions:

  • MKK3 plays a critical role in mediating inflammatory responses by regulating mitochondrial function.
  • MKK3 influences key inflammatory pathways including NF-κB, inflammasome activation, and MAP kinase signaling.
  • Targeting MKK3 may offer a novel therapeutic strategy for managing inflammatory conditions such as sepsis.
Keywords:
Acute lung injuryCaspase 1Free radicalsInflammasomeInflammationMitochondriaNF-κBOxidantsSepsis

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