How many neutrophils are enough (redux, redux)?

Silverstein, Samuel C.; Rabadán, Raúl

doi:10.1172/jci63939

Cited by 6 publications

(6 citation statements)

References 31 publications

(32 reference statements)

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“…Neutrophils are part of the first line of defense against infection and are massively recruited on damage sites ( 36 ). The defense function is mainly mediated by phagocytosis, intracellular degradation, releasing of granules, and formation of neutrophil extracellular traps (NETs) after sensing dangerous stress.…”

Section: Plasticity Of Neutrophils and Macrophages In Repairmentioning

confidence: 99%

Immune-Mediated Repair: A Matter of Plasticity

et al. 2017

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Though the immune system is generally defined as a system of defense, it is increasingly recognized that the immune system also plays a crucial role in tissue repair and its potential dysregulations. In this review, we explore how distinct immune cell types are involved in tissue repair and how they interact in a process that is tightly regulated both spatially and temporally. We insist on the concept of immune cell plasticity which, in recent years, has proved fundamental for the success/understanding of the repair process. Overall, the perspective presented here suggests that the immune system plays a central role in the physiological robustness of the organism, and that cell plasticity contributes to the realization of this robustness.

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Section: Plasticity Of Neutrophils and Macrophages In Repairmentioning

confidence: 99%

Immune-Mediated Repair: A Matter of Plasticity

et al. 2017

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“…PMNs (neutrophils) are a critical cellular element of innate host defense, as deficiency in the quality or quantity of PMNs leaves the host vulnerable to infections in humans and animals [7][8][9][10][11][12]. Previous studies have demonstrated dysfunctional neutrophils in CF [6,[13][14][15][16], including suboptimal activation [17], cleavage of CXCR1 [18], hypersensitivity to LPS stimulation [19], deviant production of reactive oxygen species [20], perturbation of genome-wide gene expression [21], alteration in inflammatory signaling [22], hyperproduction of IL-8 [23,24], delayed apoptosis [25], abnormal formation of extracellular traps [26], hyperoxidation of glutathione [27], abnormal granule release [28], and deficiencies in phagosomal chloride transport [29], HOCl production, and microbial killing [30].…”

Section: Introductionmentioning

confidence: 99%

CFTR targeting during activation of human neutrophils

Valentine

Wang

2016

Journal of Leukocyte Biology

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Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, plays critical roles in phagocytic host defense. However, how activated neutrophils regulate CFTR channel distribution subcellularly is not well defined. To investigate, we tested multiple Abs against different CFTR domains, to examine CFTR expression in human peripheral blood neutrophils by flow cytometry. The data confirmed that resting neutrophils had pronounced CFTR expression. Activation of neutrophils with soluble or particulate agonists did not significantly increase CFTR expression level, but induced CFTR redistribution to cell surface. Such CFTR mobilization correlated with cell-surface recruitment of formyl-peptide receptor during secretory vesicle exocytosis. Intriguingly, neutrophils from patients with ΔF508-CF, despite expression of the mutant CFTR, showed little cell-surface mobilization upon stimulation. Although normal neutrophils effectively targeted CFTR to their phagosomes, ΔF508-CF neutrophils had impairment in that process, resulting in deficient hypochlorous acid production. Taken together, activated neutrophils regulate CFTR distribution by targeting this chloride channel to the subcellular sites of activation, and ΔF508-CF neutrophils fail to achieve such targeting, thus undermining their host defense function.

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“…Under homeostatic conditions, a population of commensal bacteria, Sp , resides in the lumen on the apical side of the airway epithelium, where they are contained by a competent epithelial barrier integrity (Beisswenger et al, 2007 ) (Figures 1Aa,Ba ) and immune responses mediated by neutrophils and macrophages (Dick et al, 2008 ; Standish and Weiser, 2009 ) (Figures 1Ab,Bb ). Through disrupted barrier, apically located Sp can translocate to reach the blood vessel (Beisswenger et al, 2007 ) (Figures 1Ac,Bc ), where they are either killed by resident immune cells that circulate in the blood (Li et al, 2002 ; Li, 2004 ), or grow uncontrollably and result in invasive infection if the immune cells cannot contain the translocated Sp (Silverstein and Rabadan, 2012 ). The amount of the translocated Sp in the blood vessel is therefore a determinant of whether disrupted Sp -host interactions cause serious infection such as sepsis.…”

Section: Resultsmentioning

confidence: 99%

Mathematical Modeling of Streptococcus pneumoniae Colonization, Invasive Infection and Treatment

et al. 2017

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Streptococcus pneumoniae (Sp) is a commensal bacterium that normally resides on the upper airway epithelium without causing infection. However, factors such as co-infection with influenza virus can impair the complex Sp-host interactions and the subsequent development of many life-threatening infectious and inflammatory diseases, including pneumonia, meningitis or even sepsis. With the increased threat of Sp infection due to the emergence of new antibiotic resistant Sp strains, there is an urgent need for better treatment strategies that effectively prevent progression of disease triggered by Sp infection, minimizing the use of antibiotics. The complexity of the host-pathogen interactions has left the full understanding of underlying mechanisms of Sp-triggered pathogenesis as a challenge, despite its critical importance in the identification of effective treatments. To achieve a systems-level and quantitative understanding of the complex and dynamically-changing host-Sp interactions, here we developed a mechanistic mathematical model describing dynamic interplays between Sp, immune cells, and epithelial tissues, where the host-pathogen interactions initiate. The model serves as a mathematical framework that coherently explains various in vitro and in vitro studies, to which the model parameters were fitted. Our model simulations reproduced the robust homeostatic Sp-host interaction, as well as three qualitatively different pathogenic behaviors: immunological scarring, invasive infection and their combination. Parameter sensitivity and bifurcation analyses of the model identified the processes that are responsible for qualitative transitions from healthy to such pathological behaviors. Our model also predicted that the onset of invasive infection occurs within less than 2 days from transient Sp challenges. This prediction provides arguments in favor of the use of vaccinations, since adaptive immune responses cannot be developed de novo in such a short time. We further designed optimal treatment strategies, with minimal strengths and minimal durations of antibiotics, for each of the three pathogenic behaviors distinguished by our model. The proposed mathematical framework will help to design better disease management strategies and new diagnostic markers that can be used to inform the most appropriate patient-specific treatment options.

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How many neutrophils are enough (redux, redux)?

Cited by 6 publications

References 31 publications

Immune-Mediated Repair: A Matter of Plasticity

Immune-Mediated Repair: A Matter of Plasticity

CFTR targeting during activation of human neutrophils

Mathematical Modeling of Streptococcus pneumoniae Colonization, Invasive Infection and Treatment

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