title: Fever-range hyperthermia improves the anti-apoptotic effect induced by low pH on human neutrophils promoting a proangiogenic profile.
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.
authors: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Fernando Erra
authors: FE
authors: Díaz
authors: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Ezequiel
authors: E
authors: Dantas
authors: Instituto de Investigaciones Farmacológicas (ININFA), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Maia
authors: M
authors: Cabrera
authors: Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Constanza A
authors: CA
authors: Benítez
authors: Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: María V
authors: MV
authors: Delpino
authors: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Gabriel
authors: G
authors: Duette
authors: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Julia
authors: J
authors: Rubione
authors: Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Norberto
authors: N
authors: Sanjuan
authors: Instituto de Medicina Experimental (IMEX), CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors: Analía S
authors: AS
authors: Trevani
authors: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Jorge
authors: J
authors: Geffner
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D005334:Fever / Q000473:pathology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D018919:Neovascularization, Physiologic; D009504:Neutrophils / Q000473:pathology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000378:metabolism