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Febrile-range hyperthermia accelerates caspase-dependent apoptosis in human neutrophils

Ashish Nagarsekar1, Rachel S Greenberg, Nirav G Shah

  • 1Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|August 8, 2008
PubMed

Insights

Febrile-range temperatures (FRT) significantly accelerate human neutrophil apoptosis, enhancing innate immune responses. This accelerated programmed cell death at FRT may limit inflammation and tissue damage during fever.

Area of Science:

  • Immunology
  • Cell Biology
  • Pathophysiology

Background:

  • Human neutrophils (polymorphonuclear leukocytes, PMNs) are critical for innate immunity and pathogen clearance.
  • Regulated PMN apoptosis ensures efficient clearance without releasing harmful intracellular contents.
  • Understanding PMN apoptosis at different temperatures is vital for comprehending immune responses during febrile illnesses.

Purpose of the Study:

  • To investigate the effect of febrile-range temperatures (FRT) on the spontaneous apoptosis rate of human peripheral blood PMNs.
  • To elucidate the molecular mechanisms underlying FRT-induced PMN apoptosis.
  • To assess the in vivo relevance of FRT-accelerated PMN apoptosis in a mouse model.

Main Methods:

  • Culturing human PMNs at basal (37°C) and febrile-range (39.5°C) temperatures.
  • Morphological assessment of apoptosis and analysis of caspase activation (caspase-8, -3, -9).
  • Assessing mitochondrial pathway involvement (Bid cleavage, cytochrome c release) and evaluating survival factors (G-CSF, GM-CSF, IL-8).
  • Utilizing a mouse model of endotoxin-induced alveolitis to study FRT effects in vivo.

Main Results:

  • PMN apoptosis was significantly accelerated at FRT (39.5°C), with ~90% completion by 8 hours compared to 18 hours at 37°C.
  • FRT exposure rapidly activated caspase-8, followed by caspase-3 and -9, Bid cleavage, and cytochrome c release, indicating enhanced apoptosis.
  • Inhibition of key caspases protected PMNs from FRT-induced apoptosis, highlighting the role of caspase activation.
  • Survival factors (G-CSF, GM-CSF, IL-8) prolonged PMN survival but did not eliminate the temperature-dependent difference.
  • In vivo, FRT doubled the apoptosis rate of bronchoalveolar PMNs in a mouse model.

Conclusions:

  • Febrile-range temperatures enhance the rate of human PMN apoptosis through caspase-8 activation and both mitochondrial-dependent and independent pathways.
  • Accelerated PMN apoptosis at FRT may be a crucial mechanism for limiting inflammation and tissue injury during febrile conditions.
  • These findings provide insights into the immunomodulatory role of fever in host defense.

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