activation in monocytes may drive high-altitude inflammation through Fis1-linked mitochondrial stress signaling.
Evidence
Human participants, mice, myeloid-specific knockout mice, and RAW 264.7 cells were studied under real or simulated 5500 m high-altitude hypoxia, with acute 3-day cytokine increases returning to control levels after 30 days.
Caveat
The work combines human observation with mouse and cell mechanisms, so BMAL1 modulation is not yet shown to improve clinical high-altitude illness outcomes in humans.
Simplified
BACKGROUND: -induced inflammation has been implicated in the progression of high-altitude illnesses. Mitochondria are key organelles for oxygen metabolism and inflammation that are controlled by circadian clocks. However, little is known regarding how circadian clocks sense hypoxic signals and trigger downstream mitochondrial responses.
METHODS: Human participants and mice were exposed to a real or simulated high-altitude setting of 5500 m. Multichannel fluorescence intravital microscopy was used for in vivo molecular imaging of inflammation. Bioinformatics analysis, myeloid-specific knockout mice, and RAW 264.7 cells were used to investigate the underlying inflammatory mechanisms.
RESULTS: We found that high-altitude hypoxia induced dynamic inflammatory activity in monocytes, characterized by significantly increased levels of cytokines (interleukin-6 [IL-6], IL-1β and monocyte chemoattractant protein-1) after acute (3-day) exposure, which returned to control levels after a prolonged (30-day) exposure. Bioinformatics analysis revealed that the core circadian transcription factor brain and muscle Arnt-like 1 () correlated positively with hypoxia-induced inflammation in monocytes. Mechanistically, BMAL1 induced NOD-like receptor protein 3 inflammasome activation in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response. Basic helix-loop-helix family member E40, a hypoxic stress-responsive transcription factor, directly promoted Bmal1 transcription and triggered inflammation in monocytes. In contrast, myeloid-specific deletion of BMAL1 alleviated the inflammatory activity of monocytes and circulating inflammation, both in vitro and in vivo, under high-altitude hypoxia.
CONCLUSIONS: Our findings indicate that transcriptional activation of Bmal1 in monocytes can potentially serve as a novel biomarker of hypoxia-induced inflammation. Our findings also suggest a novel approach for modulating the intrinsic clock, which might render organisms less vulnerable to high-altitude hypoxia.
Key numbers
3×
Cytokine Increase
Cytokine levels in monocytes after acute exposure.
30 days
Cytokine Return
Cytokine levels normalized after prolonged exposure.
Significantly lower
M-BKO Mouse Inflammation Reduction
Inflammatory activity in compared to WT mice.
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