Abstract
Neutrophils have the shortest lifespan among leukocytes and usually die via apoptosis, limiting their deleterious potential. However, this tightly regulated cell death program can be modulated by pathogen-associated molecular patterns (PAMPs), danger-associated molecular pattern (DAMPs), and inflammatory cytokines. We have previously reported that low pH, a hallmark of inflammatory processes and solid tumors, moderately delays neutrophil apoptosis. Here we show that fever-range hyperthermia accelerates the rate of neutrophil apoptosis at neutral pH but markedly increases neutrophil survival induced by low pH. Interestingly, an opposite effect was observed in lymphocytes; hyperthermia plus low pH prevents lymphocyte activation and promotes the death of lymphocytes and lymphoid cell lines. Analysis of the mechanisms through which hyperthermia plus low pH increased neutrophil survival revealed that hyperthermia further decreases cytosolic pH induced by extracellular acidosis. The fact that two Na+/H+ exchanger inhibitors, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and amiloride, reproduced the effects induced by hyperthermia suggested that it prolongs neutrophil survival by inhibiting the Na+/H+ antiporter. The neutrophil anti-apoptotic effect induced by PAMPs, DAMPs, and inflammatory cytokines usually leads to the preservation of the major neutrophil effector functions such as phagocytosis and reactive oxygen species (ROS) production. In contrast, our data revealed that the anti-apoptotic effect induced by low pH and hyperthermia induced a functional profile characterized by a low phagocytic activity, an impairment in ROS production and a high ability to suppress T-cell activation and to produce the angiogenic factors VEGF, IL-8, and the matrix metallopeptidase 9 (MMP-9). These results suggest that acting together fever and local acidosis might drive the differentiation of neutrophils into a profile able to promote both cancer progression and tissue repair during the late phase of inflammation, two processes that are strongly dependent on the local production of angiogenic factors by infiltrating immune cells.
Highlights
Neutrophils are rapidly recruited into sites of inflammation or infection to ingest and destroy microbes through the action of oxidants, proteases, and antimicrobial proteins
We show that febrile-range hyperthermia markedly enhanced the neutrophil anti-apoptotic effect induced by low pH
Considering previous studies showing that fever-range hyperthermia decreases cytosolic pH in cancer cells,[29] we hypothesized that hyperthermia might delay apoptosis of neutrophils cultured at low pH by further lowering cytosolic pH
Summary
Neutrophils are rapidly recruited into sites of inflammation or infection to ingest and destroy microbes through the action of oxidants, proteases, and antimicrobial proteins These toxic weapons do not discriminate self from non-self and cause bystander injury in the course of a variety of pathologic conditions.[1] For this reason, the inflammatory activity of neutrophils is tightly regulated in vivo to avoid damage to the host. (a and b) Percentages of apoptotic cells were evaluated by staining with annexin-V FITC/propidium iodide and flow cytometry. Apoptosis was evaluated by staining with annexin-V FITC/propidium iodide and flow cytometry. Cells were cultured for 8 h at different pH (7.3 or 6.0) and temperatures (37 °C or 39.5 °C) and apoptosis was evaluated by staining with annexin-V FITC/propidium iodide and flow cytometry. It influences the function of monocytes, NK, and T cells.[16,17,18]
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