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.