Mechanisms of neutrophil death in human immunodeficiency virus-infected patients: role of reactive oxygen species, caspases and map kinase pathways

Abstract

SummaryNeutrophils from human immunodeficiency virus-positive (HIV + ) patients have an increased susceptibility to undergo programmed cell death (PCD), which could explain neutropenia during advanced disease. In this work, key steps of PCD have been evaluated in neutrophils from HIV + patients. The role of caspase-3, caspase-8, mitogen activated protein kinase (MAPK) and reactive oxygen species (ROS) was analysed. Spontaneous neutrophil death is dependent upon caspase-3 but independent of caspase-8, suggesting that the intrinsic pathway is involved as a pathogenic mechanism of PCD. Inhibition of ROS decreased spontaneous PCD and caspase-3 hydrolysis, connecting oxidative stress and caspase-3 activation with neutrophil PCD in HIVinfected patients. Additionally, an increased neutrophil death was observed in HIV + patients, following inhibition of p38 MAPK, suggesting a role for p38 MAPK in cell survival during the disease. We conclude that oxidative stress secondary to HIV infection can accelerate neutrophil death.

Characterization of neutrophil extracellular traps in cats naturally infected with feline leukemia virus

“…Furthermore, MPO activity increased in unstimulated neutrophils from FeLV + symptomatic animals compared with healthy ones, implying spontaneous neutrophil activation during progressive FeLV infection. Altered neutrophil functions have been detected in other viral infections, particularly with human immunodeficiency virus type 1 and human T-lymphotropic virus type 1 (Guerreiro et al, 2005;Salmen et al, 2007). An increase in NET release and MPO activity in unstimulated neutrophils from FeLV + symptomatic cats was also observed, suggesting that progressive viral infections may induce chronic neutrophil activation.…”

Interactions between Human Immunodeficiency Virus Type 1 and Polymorphonuclear Neutrophils

“…PMN apoptosis is accelerated as soon as the early stages of untreated HIV infection [60,61,62,63,64]. Downregulation of proinflammatory capacity has also been reported during PMN apoptosis [65].…”

“…This spontaneous PMN death is dependent on caspase-3 but independent of caspase-8, suggesting that the intrinsic pathway is involved in PMN death. Spontaneous death of PMN from HIV-infected patients was also reduced upon incubation with catalase/SOD, which is known to reduce ROS levels, suggesting that the underlying mechanism may be related to increased basal ROS production [63]. Several studies suggest that ROS affect the intrinsic apoptotic pathway, probably by targeting mitochondria.…”

“…ROS might also promote apoptosis by interfering with the activation of survival pathways mediated by NF-κB and MAPKs [68]. This process might affect the ERK [61] and P38 MAPK [63] pathways, resulting in a PMN apoptosis/survival imbalance.…”

Activation of NK cells by HIV-specific ADCC antibodies

“…On the other hand, granulocytes are frequently depleted and have high levels of apoptosis during HIV and SIV infection. [28][29][30] An initial role for neutrophils in HIV infection was postulated in the context of increased susceptibility of HIV-infected individuals to bacterial and fungal infections in neutropenic subjects. 31 More recent results suggest additional roles for neutrophils given that neutrophils express several anti-viral factors, such as α-defensins and lactoferrin, which have anti-HIV-1 activity, possibly suggesting a protective role for neutrophils in HIV-1.…”