Receptors recognizing the Fc-part of immunoglobulins (FcR) are important in the engagement of phagocytes with opsonized micro-organisms, but they also play a major role in the pathogenesis of chronic ...inflammatory diseases. Different FcRs are specifically recognizing and binding the different classes of immunoglobulins, transmitting different signals into the cell. The function of IgG (FcγR's) and IgA (FcαR) recognizing receptors is controlled by cellular signals evoked by activation of heterologous receptors in a process generally referred to as inside-out control. This concept is clearly described for the regulation of integrin receptors. Inside-out control can be achieved at different levels by modulation of: (i) receptor affinity, (ii) receptor avidity/valency, (iii) interaction with signaling chains, (iv) interaction with other receptors and (v) localization in functionally different membrane domains. The inside-out control of FcRs is an interesting target for novel therapy by therapeutical antibodies as it can potentiate or decrease the functionality of the response to the antibodies depending on the mechanisms of the diseases they are applied for.
Neutrophil phenotypes in health and disease Hellebrekers, Pien; Vrisekoop, Nienke; Koenderman, Leo
European journal of clinical investigation,
November 2018, Volume:
48, Issue:
S2
Journal Article
Peer reviewed
Open access
Neutrophils are one of the most important effector cells of the innate immune response (1). They are traditionally seen as a homogenous population of short‐lived cells mainly involved in the defence ...against extracellular microorganisms by phagocytosis and intracellular killing (1,2). The cells contain a large armamentarium that aids in this function and ranges from the production of reactive oxygen species by a membrane‐bound NADPH oxidase to cytotoxic proteins and peptides residing in the different granules present in the cytoplasm (3). Recently, the view of neutrophils belonging to a homogenous population of cells has been challenged, and several neutrophil phenotypes have been described that exhibit specialized functions, such as involvement in tissue repair, tumour killing and immune regulation (4). It is not clear whether these cells belong to separate parallel lineages originating from the bone marrow or that neutrophils become instructed in the distant tissues, thus changing their phenotypes. In addition, functional heterogeneity in a phenotypically homogenous population of neutrophils adds to the complexity of neutrophil phenotypes(5). This article will review the current literature describing the heterogeneity within the neutrophil compartment with respect to both phenotype and function in health and disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Neutrophils are main players in the effector phase of the host defense against micro-organisms and have a major role in the innate immune response. Neutrophils show phenotypic heterogeneity and ...functional flexibility, which highlight their importance in regulation of immune function. However, neutrophils can play a dual role and besides their antimicrobial function, deregulation of neutrophils and their hyperactivity can lead to tissue damage in severe inflammation or trauma. Neutrophils also have an important role in the modulation of the immune system in response to severe injury and trauma. In this review we will provide an overview of the current understanding of neutrophil subpopulations and their function during and post-infection and discuss the possible mechanisms of immune modulation by neutrophils in severe inflammation.
On the origin of low‐density neutrophils Hassani, Marwan; Hellebrekers, Pien; Chen, Na ...
Journal of leukocyte biology,
20/May , Volume:
107, Issue:
5
Journal Article
Peer reviewed
Open access
Here we elaborate on the origin of low(er)‐density neutrophils (LDNs) to better understand the variation found in literature. Supplemented with original data, we test the hypothesis that buoyant ...density of neutrophils is characterized by a spectrum that as a whole shifts to a lower density after activation. Both the 20% highest density (HDNs) and 20% lowest density (LDNs) neutrophils from healthy donors were isolated by Percoll of different densities. Using this method we found that LDNs were significantly better in T‐cell suppression and bacterial containment than their 20% highest density counterparts. We found no statistically relevant differences in neutrophil survival or bacterial phagocytosis. Stimulation of healthy donor neutrophils with N‐formyl‐methionyl‐leucyl‐phenylalanine induced LDNs co‐segregating with peripheral blood mononuclear cells after Ficoll separation. These in vitro induced LDNs showed increased activation markers compared to HDNs and were comparable to the activation markers found on the LDN fraction seen in patients with chronic inflammatory conditions such as present in cancer patients. This all fits with the hypothesis that the density of neutrophils is distributed in a spectrum partially coupled to maturation. Additionally a shift in this spectrum can be induced by in vitro stimulation or by activation in disease.
Nowadays the term low(er) density neutrophils (LDN) is used to describe a specific subset of neutrophils with a certain buoyant density, but these LDNs are characterized by a wide variety in both functional and morphologic properties, especially in disease.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not ...over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Critically ill post-surgical, post-trauma and/or septic patients are characterised by severe inflammation. This immune response consists of both a pro- and an anti-inflammatory component. The ...pro-inflammatory component contributes to (multiple) organ failure whereas occurrence of immune paralysis predisposes to infections. Strikingly, infectious complications arise in these patients despite the presence of a clear neutrophilia. We propose that dysfunction of neutrophils potentially increases the susceptibility to infections or can result in the inability to clear existing infections. Under homeostatic conditions these effector cells of the innate immune system circulate in a quiescent state and serve as the first line of defence against invading pathogens. In severe inflammation, however, neutrophils are rapidly activated, which affects their functional capacities, such as chemotaxis, phagocytosis, intra-cellular killing, NETosis, and their capacity to modulate adaptive immunity. This review provides an overview of the current understanding of neutrophil dysfunction in severe inflammation. We will discuss the possible mechanisms of downregulation of anti-microbial function, suppression of adaptive immunity by neutrophils and the contribution of neutrophil subsets to immune paralysis.
Review of how distinct neutrophil phenotypes at the site of inflammation necessitate more specific future anti‐neutrophil therapy.
In severe, neutrophilic asthma, neutrophils are thought to have an ...important role in both the maintenance of the disease and during exacerbations. These patients often display excessive, mucosal airway inflammation with unresolving neutrophilia. Because this variant of asthma is poorly controlled by glucocorticoids, specific pharmacologic targeting of neutrophils seems a plausible therapeutic approach. However, most attempts with this approach have failed in the clinic. We propose that this could be attributed, in part, to an incomplete understanding of the emerging new insights underlying neutrophil homeostasis and life span, neutrophil reverse transmigration, neutrophil phenotypes, and neutrophil transdifferentiation in human health and disease. Of clinical relevance, recent translational studies have started to uncover distinct neutrophil subsets in humans, namely mature and hypersegmented phenotypes that have bimodal immunomodulatory functions during an acute inflammatory response. In this review, we will elaborate on some of the novel insights in neutrophil biology and attempt to translate them into potential consequences for pharmacologic intervention of severe neutrophilic asthma. We speculate that the disease‐relevant neutrophil phenotype should be targeted selectively without compromising the immunomodulatory functions essential for homeostasis and pulmonary immunity. However, the identity and exact functional role of distinct neutrophil phenotypes in inflammatory diseases of the human airway remain elusive.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression ...through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.
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