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Structured models of ontogenic, phenotypic and functional diversity have been instrumental for a renewed understanding of the biology of immune cells, such as macrophages and lymphoid cells. However, there are no established models that can be used to define the diversity of neutrophils, the most abundant myeloid cells. This lack of an established model is largely due to the uniquely short lives of neutrophils, a consequence of their inability to divide once terminally differentiated, which has been perceived as a roadblock to functional diversity. This perception is rapidly evolving as multiple phenotypic and functional variants of neutrophils have been found, both in homeostatic and disease conditions. In this Opinion article, we present an overview of neutrophil heterogeneity and discuss possible mechanisms of diversification, including genomic regulation. We suggest that neutrophil heterogeneity is an important feature of immune pathophysiology, such that co-option of the mechanisms of diversification by cancer or other disorders contributes to disease progression.Emerging data indicate that neutrophils exist in several different ‘flavours’. Here, the authors outline potential underlying mechanisms for the presence of distinct neutrophil subsets in health and disease.

Neutrophils are formidable defenders. Their vast numbers, constant production, high cytotoxicity and capacity to produce extracellular traps, underlie their ability to efficiently protect in a microorganism-rich world. However, neutrophils are much more than immune sentinels, as evidenced by the expanding repertoire of functions discovered in the context of tissue homeostasis, regeneration or chronic pathologies. In this Perspective, we discuss general functional features of the neutrophil compartment that may be relevant in most, if not all, physiological scenarios in which they participate, including specialization in naïve tissues, transcriptional noise in the bloodstream as a potential strategy for diversification and functional bias in inflammatory sites. We intentionally present the reader with more questions than answers and propose models and approaches that we hope will shed new light onto the biology of these fascinating cells and spark new directions of research. Hidalgo and colleagues discuss general functional features of the neutrophil compartment that may be relevant in physiological scenarios such as specialization in naïve tissues, diversification and functional bias in inflammatory sites.

At the core of this technical limitation lies the unique biology of these cells: neutrophils feature short life spans, low transcriptional activity and low abundance in certain tissues and physiological contexts, altogether explaining why they have been missed or neglected in conventional single-cell analytical pipelines, especially in human samples.4 This can be problematic, as these leukocytes dominate the immunological landscape of many solid tumours and have been associated with poor disease outcomes in patients with cancer.5 Further, recent studies have demonstrated that neutrophils, like other myeloid cells, are highly heterogeneous and capable of transcriptional rewiring, thus challenging the prevailing perception of short life and poor transcriptional plasticity. Whether they prevent tumour development or actively support the progression of this disease is still a matter of debate, but it is likely that different activation states of neutrophils exert specialised functions in the tumour microenvironment. [...]single-cell analyses of pancreatic tumours may be instrumental to identify and report the diversity and particular features of neutrophils, with the hope that they will illuminate potential vulnerabilities of the immune microenvironment that can be harnessed to prevent tumorous progression. Gain-of-function and loss-of-function experiments, as well as chromatin immunoprecipitation (ChIP)-qPCR assays using HL-60 cells (a promyelocytic cell line that can be differentiated into neutrophils in vitro), validated the direct regulation of TAN-1 genes by BHLHE40.

Rhythms in immunity manifest in multiple ways, but perhaps most prominently by the recurrent onset of inflammation at specific times of day. These patterns are of importance to understand human disease and are caused, in many instances, by the action of neutrophils, a myeloid leukocyte with striking circadian features. The neutrophil's short life, marked diurnal variations in number, and changes in phenotype while in the circulation, help explain the temporal features of inflammatory disease but also uncover core features of neutrophil physiology. Here, we summarize well-established concepts and introduce recent discoveries in the biology of these cells as they relate to circadian rhythms. We highlight that although the circadian features of neutrophils are better known and relevant to understand disease, they may also influence important aspects of organ function even in the steady-state. Finally, we discuss the possibility of targeting these temporal features of neutrophils for therapeutic benefit.

The infiltration of naïve tissues by myeloid cells has been long related to their clearance and the physiological cell turnover, however, increasing evidence shows that they can additionally fulfill specific, non-immune functions in different tissues. There is also growing evidence to support that infiltrated granulocytes and monocytes respond to different environments by modulating gene expression and cytokine production, which in turn contribute to the normal function of the host tissue. This review will address the roles of immigrated myeloid cells in different tissues and their crosstalk with the host tissue environments.

The innate immune response to bacterial infections requires the interaction of neutrophils and platelets. Here, we show that a multistep reciprocal crosstalk exists between these two cell types, ultimately facilitating neutrophil influx into the lung to eliminate infections. Activated platelets adhere to intravascular neutrophils through P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1)-mediated binding, a primary interaction that allows platelets glycoprotein Ibα (GPIbα)-induced generation of neutrophil-derived extracellular vesicles (EV). EV production is directed by exocytosis and allows shuttling of arachidonic acid into platelets. EVs are then specifically internalized into platelets in a Mac1-dependent fashion, and relocated into intracellular compartments enriched in cyclooxygenase1 (Cox1), an enzyme processing arachidonic acid to synthesize thromboxane A 2 (TxA 2 ). Finally, platelet-derived-TxA 2 elicits a full neutrophil response by inducing the endothelial expression of ICAM-1, intravascular crawling, and extravasation. We conclude that critical substrate–enzyme pairs are compartmentalized in neutrophils and platelets during steady state limiting non-specific inflammation, but bacterial infection triggers regulated EV shuttling resulting in robust inflammation and pathogen clearance. Interaction between platelets and neutrophils promotes neutrophil activation. Here the authors show that neutrophils initiate the cross-talk with platelets by shuttling arachidonic acid via extracellular vesicles, which platelets convert to thromboxane A 2 that then elicits neutrophil activation.

Neutrophils display distinct gene expression patters depending on their developmental stage, activation state and tissue microenvironment. To determine the transcription factor networks that shape these responses in a mouse model, we integrated transcriptional and chromatin analyses of neutrophils during acute inflammation. We showed active chromatin remodeling at two transition stages: bone marrow–to-blood and blood-to-tissue. Analysis of differentially accessible regions revealed distinct sets of putative transcription factors associated with control of neutrophil inflammatory responses. Using ex vivo and in vivo approaches, we confirmed that RUNX1 and KLF6 modulate neutrophil maturation, whereas RELB, IRF5 and JUNB drive neutrophil effector responses and RFX2 and RELB promote survival. Interfering with neutrophil activation by targeting one of these factors, JUNB, reduced pathological inflammation in a mouse model of myocardial infarction. Therefore, our study represents a blueprint for transcriptional control of neutrophil responses in acute inflammation and opens possibilities for stage-specific therapeutic modulation of neutrophil function in disease. Neutrophils demonstrate highly dynamic functional and transcriptional changes depending on their tissue environment. Udalova and colleagues use an inflammation model to examine neutrophils and find that the transcription factors RUNX1 and KLF6 control maturation; RELB, IRF5 and JUNB drive effector responses; and RFX2 and RELB promote survival.

Key Points Neutrophils are primarily produced in the bone marrow through a process that is highly dependent on granulocyte colony-stimulating factor (G-CSF). However, changes that are associated with chronic inflammation, such as psychosocial stress, hyperlipidaemia and hyperglycaemia, can stimulate extramedullary neutrophil production and increase neutrophil numbers in the blood. The function of circulating neutrophils is modified by the presence of risk factors for chronic inflammation. Ageing of the host impairs neutrophil migration, whereas metabolic changes can prime neutrophils for activation. The interaction of neutrophils and platelets along the luminal aspect of sites of inflammation is essential for fine-tuning neutrophil recruitment. Neutrophil secretory products, partly in conjunction with platelet-derived proteins, deliver molecular cues to stimulate secondary monocyte recruitment. Neutrophils and macrophages form an intricate partnership at sites of damage. During the inflammation phase, neutrophils enhance macrophage activities that are aimed at eliminating the initiating stimulus. During the resolution phase, dying neutrophils convey an important signal that reprogrammes macrophages to promote healing. Neutrophils have recently been shown to be important in chronic inflammatory diseases, including neurodegenerative diseases and atherosclerosis. Relevant mechanisms include their interplay with the monocyte lineage — for example, the enhancement of monocyte recruitment and the activation of macrophages — and their direct pro-inflammatory effects, such as release of reactive oxygen species and neutrophil extracellular traps (NETs), and neutrophil-derived proteolytic activity. Neutrophil-instructed chronic inflammation can be targeted by inhibiting NET release or by breaking down NETs, by translating recent findings about neutrophil recruitment during chronic inflammation and by promoting the clearance of apoptotic neutrophils. In addition, neutrophil-derived microparticles that elicit anti-inflammatory responses represent an innovative strategy to reduce inflammation. Neutrophils are rapidly recruited to tissues in response to injury or infection, and they have mainly been studied in the context of acute inflammation. However, neutrophils can also be important contributors to chronic tissue inflammation. This Review discusses neutrophil function in the context of chronic inflammation and considers the potential of targeting these cells in chronic diseases. Traditionally, neutrophils have been acknowledged to be the first immune cells that are recruited to an inflamed tissue and have mainly been considered in the context of acute inflammation. By contrast, their importance during chronic inflammation has been studied in less depth. This Review aims to summarize our current understanding of the roles of neutrophils in chronic inflammation, with a focus on how they communicate with other immune and non-immune cells within tissues. We also scrutinize the roles of neutrophils in wound healing and the resolution of inflammation, and finally, we outline emerging therapeutic strategies that target neutrophils.

Genetic polymorphisms affect expression of the atypical chemokine receptor ACKR1 (Duffy) on nucleated erythrocyte precursors. Rot and colleagues show that loss of its expression alters hematopoiesis, yielding a distinct neutrophil population that rapidly exits the bloodstream to give an apparent ‘neutropenia’ phenotype. Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 ( ACKR1 ). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa.

The importance of β2 integrins for immune function is shown by rare genetic disorders (Leukocyte adhesion deficiencies, or LAD) that affect their expression (LAD-I) or function (LAD-III, caused by mutations in the integrin regulator, kindlin-3) (8,9). Because of these various roles in immunity, β2 integrin dysfunction can contribute to the development of both immunodeficiency diseases and inflammatory diseases. Focusing on the migratory dynamics of neutrophils,Morikis and Simonsummarize an extensive body of literature suggesting that biomechanical signals at the original site of interactions between leukocytes and the activated endothelium critically regulate leukocyte adhesion and polarization. Because the presence of both signals display potent circadian patterns, the review also discusses how these signals contribute to diurnal rhythms in leukocyte trafficking. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1.VestweberD.How leukocytes cross the vascular endothelium.Nat Rev Immunol.