Neutrophils: Molecules, Functions and Pathophysiological Aspects

Witko‐Sarsat, Véronique; Rieu, Philippe; Descamps‐Latscha, Béatrice; Lesavre, Philippe; Halbwachs‐Mecarelli, Lise

doi:10.1038/labinvest.3780067

Cited by 938 publications

(761 citation statements)

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“…Neutrophils are cells of the innate immune system that play an essential role in antimicrobial defense via the release of numerous toxic mediators [3]. In addition, extensive research has now clearly established that the release of chemokines and cytokines constitutes yet another key contribution of neutrophils to innate immunity (reviewed in reference [4]).…”

Section: Introductionmentioning

confidence: 99%

“…CXCL10 mediates its various activities by binding to CXCR3 expressed on activated Th1 and NK cells [1], and influences the behavior of nonimmune cells that express a CXCR3. For instance, it inhibits endothelial cell proliferation through interfering with the function of receptors for the growth factors, basic fibroblast growth factor and vascular endothelial growth factor, resulting in the inhibition of angiogenesis [2].Neutrophils are cells of the innate immune system that play an essential role in antimicrobial defense via the release of numerous toxic mediators [3]. In addition, extensive research has now clearly established that the release of chemokines and cytokines constitutes yet another key contribution of neutrophils to innate immunity (reviewed in reference [4]).…”

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Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

et al. 2007

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The CXCL10 chemokine is a critical chemoattractant for the recruitment of activated Th1 and NK cells into inflammatory sites. CXCL10 is typically produced by myeloid cells in response to IFN-c, as well as by neutrophils, though the latter require a costimulation with IFN-c and LPS. In this study, we investigated the molecular mechanism(s) whereby IFN-c and TLR4 ligation synergize to induce CXCL10 expression in neutrophils. By primary transcript real-time PCR analysis, we demonstrate that the CXCL10 gene is transcriptionally induced by the LPS plus IFN-c combination in neutrophils, consistent with previous studies showing that increased CXCL10 gene expression does not reflect enhanced mRNA stability. The IFN-c-induced STAT1 activation and the lipopolysaccharide (LPS)-induced NF-jB activation were not enhanced if neutrophils were exposed to both stimuli, whereas both transcription factors were activated by IFN-c or LPS in monocytes. Finally, pharmacological inhibitors of NF-jB demonstrated its role in the induction of CXCL10 expression by LPS plus IFN-c in neutrophils, and by LPS or IFN-c in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN-c toward CXCL10 gene expression likely reflects the cooperative induction of the NF-jB and STAT1 transcription factors by LPS and IFN-c, respectively. IntroductionCXCL10/IFN-c-inducible protein 10 (IP-10) is a critical component of several immune responses, acting notably as a chemoattractant for activated NK and Th1 cells into sites of inflammation. CXCL10 mediates its various activities by binding to CXCR3 expressed on activated Th1 and NK cells [1], and influences the behavior of nonimmune cells that express a CXCR3. For instance, it inhibits endothelial cell proliferation through interfering with the function of receptors for the growth factors, basic fibroblast growth factor and vascular endothelial growth factor, resulting in the inhibition of angiogenesis [2].Neutrophils are cells of the innate immune system that play an essential role in antimicrobial defense via the release of numerous toxic mediators [3]. In addition, extensive research has now clearly established that the release of chemokines and cytokines constitutes yet another key contribution of neutrophils to innate immunity (reviewed in reference [4]). Among the chemokines produced by neutrophils both in vitro and in vivo, CXCL10 stands out as being somewhat peculiar in terms of its induction characteristics, as originally shown by us [5,6] as well as by other groups [7][8][9]. Indeed, CXCL10 expression occurs in vitro only if However, the molecular bases of the particular inducibility of CXCL10 in human neutrophils have only been partially elucidated thus far. In this regard, we have recently clarified that the reason explaining the inability of LPS to induce CXCL10 mRNA expression in neutrophils reflects the fact that in this cell type, LPS is unable to mobilize the intracellular MyD88-independent pathway upon TLR4 binding [11]. As a result, LPS fails to...

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Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

et al. 2007

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“…Neutrophils (PMNs), the most abundant circulating leukocyte in healthy humans, and are primary effector cells that provide host defense by migrating to sites of infection [11,12]. It is clear that PMNs play a role in Leishmania infections, but their effect on disease outcome remains unclear [5,6,8,13].…”

Section: Introductionmentioning

confidence: 99%

Infection and Activation of Human Neutrophils with Fluorescent Leishmania infantum

Cj²,

2016

J Immunol Tech Infect Dis

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Neutrophils (PMNs) are recruited in high numbers to sites of host infection by the protozoan parasites of the genus Leishmania. Although PMNs are capable of phagocytizing Leishmania parasites and are potent producers of anti-microbial compounds including reactive oxygen species (ROS), they are unable to control the establishment of infection. Prior studies document production of ROS in isolated PMNs incubated with Leishmania under conditions allowing phagocytosis, but without a measure of single cells’ responses it cannot be discerned whether PMN activation and ROS production is suppressed or ineffective in the cells that internalize the parasite. To address these interactions, we engineered a strain of fluorescent, mCherry-expressing Leishmania infantum (mCherry-Li). By infecting isolated human PMNs in vitro with mCherry-Li, we observed ready association of the parasites with PMNs in a time- and dose-dependent fashion. We also examined production of PMN ROS (using the fluorescent compound DHR123) and PMN activation (as evidence by loss of surface CD62L expression). Whereas many Li-associated (mCherry+) PMNs responded to parasite interactions and uptake with ROS production and/or activation, a proportion exhibited neither response. Furthermore, a large proportion of mCherry - “bystander” PMNs displayed both ROS production and activation. The heterogeneous response of PMNs to Leishmania exposure leads us to hypothesize, first, that some PMNs exhibit decreased activation upon phagocytosis of Leishmania, and could support their maintenance. Second, responses of bystander PMNs may contribute to a local inflammatory environment that is ineffective at parasite clearance.

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“…De meilleures stratégies pourraient consister à augmenter l'efficacité des systèmes de régulation endogènes à l'origine de la sécrétion de molécules anti-inflammatoires. Après un bref rappel des fonctions pro-inflammatoires du neutrophile, cet article mettra l'accent sur les capacités qu'ont ces cellules d'arrêter le processus d'inflammation et l'état de la recherche sur les mécanismes en cause.Le polynuléaire neutrophile, une première ligne de défense pour l'organisme Fonctions de base des PN : élimination des agents infectieux L'action anti-infectieuse du neutrophile repose sur ses capacités de migration transendothéliale, de phagocytose, « d'explosion oxydative » et de dégranulation [1]. De manière physiologique, les PN transitent dans la circulation sanguine en « roulant » sur les cellules endothéliales de la paroi vasculaire (processus de rolling).…”

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“…Le polynuléaire neutrophile, une première ligne de défense pour l'organisme Fonctions de base des PN : élimination des agents infectieux L'action anti-infectieuse du neutrophile repose sur ses capacités de migration transendothéliale, de phagocytose, « d'explosion oxydative » et de dégranulation [1]. De manière physiologique, les PN transitent dans la circulation sanguine en « roulant » sur les cellules endothéliales de la paroi vasculaire (processus de rolling).…”

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Le neutrophile : ennemi ou ami ?

Dumas

Pouliot

2009

Med Sci (Paris)

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Les polynucléaires neutrophiles (PN) sont des agents de premier plan de l'immunité innée, particulièrement lors de la réaction inflammatoire ; ils sont souvent les premiers leucocytes à migrer en grand nombre vers le site enflammé. La réaction inflammatoire est le plus souvent protectrice car elle participe à la défense naturelle de l'organisme et à la réparation des tissus lésés. Malheureusement, si elle est inadaptée ou mal régulée, l'inflammation peut devenir nocive. Ainsi le neutrophile est mis en cause dans la pathogenèse de nombreuses maladies inflammatoires chroniques, comme la polyarthrite rhumatoïde et, en particulier, pour les altérations qu'il cause aux tissus et la dégradation des articulations qui en résulte. Les traitements anti-inflammatoires classiques parviennent à atténuer les symptômes de l'inflammation comme la fièvre, la douleur et l'enflure mais aucun ne permet la guérison. Plusieurs indices suggèrent qu'ils n'empêchent pas l'action destructrice des neutrophiles et pourraient même aggraver la progression des dommages. De meilleures stratégies pourraient consister à augmenter l'efficacité des systèmes de régulation endogènes à l'origine de la sécrétion de molécules anti-inflammatoires. Après un bref rappel des fonctions pro-inflammatoires du neutrophile, cet article mettra l'accent sur les capacités qu'ont ces cellules d'arrêter le processus d'inflammation et l'état de la recherche sur les mécanismes en cause.Le polynuléaire neutrophile, une première ligne de défense pour l'organisme Fonctions de base des PN : élimination des agents infectieux L'action anti-infectieuse du neutrophile repose sur ses capacités de migration transendothéliale, de phagocytose, « d'explosion oxydative » et de dégranulation [1]. De manière physiologique, les PN transitent dans la circulation sanguine en « roulant » sur les cellules endothéliales de la paroi vasculaire (processus de rolling). En réponse à la détection de produits bactériens (peptides formylés, lipopolysaccharides) ou sous l'influence de molécules attractives [leucotriène (LT)B 4 , la chimiokine CXCL8 ou IL(interleukine)-8, fragments du complément, etc.], le PN exprime à sa surface des molécules d'adhé-rence qui vont lui permettre de traverser la paroi endothéliale et de migrer vers le site enflammé. Il reconnaît spécifiquement des motifs présents à la surface des micro-organismes (bactéries, virus), ce qui déclenche leur phagocytose. La dégradation des pathogènes ainsi ingérés s'effectue par deux mécanismes concomitants : la production de formes réactives de l'oxygène (ROS : reactive oxygen species) par la NADPH oxydase et la libé-ration, par les granules des PN, de protéines enzymatiques (myéloperoxydase, élastases, lysosyme, gélatinase)

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Neutrophils: Molecules, Functions and Pathophysiological Aspects

Cited by 938 publications

References 412 publications

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

Infection and Activation of Human Neutrophils with Fluorescent Leishmania infantum

Le neutrophile : ennemi ou ami ?

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