Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease.
ABSTRACT Neutrophils are the most abundant cell type involved in the innate immune response. They are rapidly recruited to sites of injury or infection where they engulf and kill invading microorganisms. Neutrophil apoptosis, the process of programmed cell death that prevents the release of neutrophil histotoxic contents, is tightly regulated and limits the destructive capacity of neutrophil products to surrounding tissue. The subsequent recognition and phagocytosis of apoptotic cells by phagocytic cells such as macrophages is central to the successful resolution of an inflammatory response and it is increasingly apparent that the dying neutrophil itself exerts an anti-inflammatory effect through modulation of surrounding cell responses, particularly macrophage inflammatory cytokine release. Apoptosis may be delayed, induced or enhanced by micro-organisms dependent on their immune evasion strategies and the health of the host they encounter. There is now an established field of research aimed at understanding the regulation of apoptosis and its potential as a target for therapeutic intervention in inflammatory and infective diseases. This review focuses on the physiological regulation of neutrophil apoptosis with respect to the innate immune system and highlights recent advances in mechanistic understanding of apoptotic pathways and their therapeutic manipulation in appropriate and excessive innate immune responses.
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ABSTRACT: OBJECTIVE: Reduced CD16 expression is associated with neutrophil apoptosis. This study aimed to compare CD16 expression on neutrophils in the vagina from women with normal bacterial flora and with vaginitis. STUDY DESIGN: Vaginal lavages were sampled from volunteers diagnosed with bacterial vaginosis (BV, n=34), vulvovaginal candidiasis (VC, n=43), BV plus VC (BV+VC, n=14), and normal flora (NF, n=51). Neutrophils were identified by expression of CD15, CD16 and CD24 surface markers as assessed by flow cytometry. RESULTS: CD16 expression was elevated in neutrophils from women with vaginitis (BV p<0.0001; VC p=0.01; BV+VC p=0.0027) as compared to women with NF. CONCLUSION: The reduction in CD16 down-regulation is consistent with prolonged neutrophil viability and activity in the vagina of women with vaginitis. This may contribute to greater microbial clearance and, conversely, with inflammation-associated pathology.European journal of obstetrics, gynecology, and reproductive biology 12/2012; · 1.97 Impact Factor
Article: Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.[show abstract] [hide abstract]
ABSTRACT: We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.Cell Death & Disease 02/2013; · 5.33 Impact Factor
Article: Human neutrophil migration and activation by BJcuL, a galactose binding lectin purified from Bothrops jararacussu venom.[show abstract] [hide abstract]
ABSTRACT: Neutrophil migration to an inflamed site constitutes the first line of the innate immune response against invading microorganisms. Given the crucial role of endogenous lectins in neutrophil mobilization and activation, lectins from exogenous sources have often been considered as putative modulators of leukocyte function. Lectins purified from snake venom have been described as galactoside ligands that induce erythrocyte agglutination and platelet aggregation. This study evaluated human neutrophil migration and activation by C-type lectin BJcuL purified from Bothrops jararacussu venom. Utilizing fluorescence microscopy, we observed that biotinylated-BJcuL was evenly distributed on the neutrophil surface, selectively inhibited by D-galactose. Lectin was able to induce modification in the neutrophil morphology in a spherical shape for a polarized observed by optical microscopy and exposure to BJcuL in a Boyden chamber assay resulted in cell migration. After 30 minutes of incubation with BJcuL we found enhanced neutrophil functions, such as respiratory burst, zymozan phagocytosis and an increase in lissosomal volume. In addition, BJcuL delays late apoptosis neutrophils. These results demonstrate that BJcuL can be implicated in a wide variety of immunological functions including first-line defense against pathogens, cell trafficking and induction of the innate immune response since lectin was capable of inducing potent neutrophil activation.BMC Immunology 01/2011; 12:10. · 2.53 Impact Factor