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Key Points The current view of the neutrophil as a short-lived, homogeneous cell type with a role limited to the elimination of pathogens during the innate immune response has begun to change. Recent studies have revealed that the lifespan of a neutrophil in circulation might be much longer, and that differential subpopulations of neutrophils and their reservoirs (marginal pools) might exist (although it still remains to be determined whether these subpopulations are functional or lineage-restricted). The classical cascade of neutrophil recruitment has been updated recently to reflect our better understanding of how this process occurs in the blood under shear stress conditions (for example, neutrophils have been found to form tethers and slings to anchor themselves to the vasculature). In addition, our understanding has improved regarding what are preferable sites of neutrophil extravasation. It is also now clear that there are exceptions to this classical cascade in a number of organs, such as the liver, lung and brain, where some steps of the cascade do not occur and/or different molecules are used by neutrophils. Furthermore, we recognize there might be differences between sterile and infectious inflammation. Once extravasated, neutrophils follow a hierarchy of chemotactic molecules to reach the site of inflammation, following first 'intermediate' chemoattractants (endogenous chemokines) and then later 'end-target' chemoattractants (bacterial peptides or complement components). The process of chemotaxis is controlled by multiple intracellular signalling pathways (mitogen-activated protein kinase-dependent) controlling 'go' and 'stop' signals. Despite the pre-existing dogma that neutrophils leave the vasculature and die, it has been revealed that some extravasated neutrophils might re-enter circulation, leading to the dissemination of inflammation to other organs and subsequent tissue injury. In other cases, transmigrating cells may play an important part in the resolution of inflammation. In fact, neutrophils were shown to participate in wound healing and to actively limit self-recruitment through the release of endogenous molecules that inhibit integrin activation or cytoskeletal changes. Newly described roles of neutrophils cover their involvement in adaptive immunity by controlling the activation of T and B cells, and through the presentation of antigens to professional antigen-presenting cells in lymph nodes. Neutrophil extracellular trap (NET) formation, a strategy of pathogen eradication discovered less than a decade ago, has now been described to occur in vivo not only during acute (bacterial or viral) inflammation but also in numerous pathological conditions, such as autoimmune diseases, vascular diseases and cancer. Recently described mechanisms of NET formation indicate that neutrophils releasing NETs in vivo do not immediately die but rather keep performing functions such as chemotaxis and phagocytosis. It is becoming clear that the immune functions of neutrophils are more complex than once thought. Here, the authors provide an updated version of the classical neutrophil recruitment cascade and discuss the pro-inflammatory and anti-inflammatory roles of these cells in different immune settings. Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

Objectives: To evaluate the relationship between different serum oxidative markers and the delta neutrophil index and hyperemesis gravidarum. Methods: One hundred pregnant women were enrolled in the study and divided into two groups. Group 1 included 50 women with hyperemesis gravidarum, while Group 2 (control group) included 50 pregnant women similar in age, gestational week, and body mass index. Serum oxidative markers and complete blood count inflammatory markers were compared. Results: Native thiol and total thiol were significantly lower in the Group 1 when compared with the control group (P=0.029 for native thiol; P=0.035 for total thiol). Moreover, ischemia-modified albumin (IMA) and catalase values were significantly higher in the Group 1 than in the control group (P=0.023 for IMA; P=0.021 for catalase). Index1% shows the disulfide/native thiol percent ratio and means that the Group 1 oxidant load is increased but not statistically significant. Myeloperoxidase, ferroxidase, and the delta neutrophil index did not differ significantly between the two groups (P=0.591, P=0.793, and P=0.52; respectively). Conclusions: According to our study, contrary to the literature, although there are differences in some values, when evaluated individually hyperemesis gravidarum does not impose an extra burden on maternal oxidant-antioxidant balance.

Among patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, plasma exchange did not reduce the incidence of death or end-stage kidney disease. A reduced-dose regimen of oral glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD.

Key Points Complementary models have been developed to study neutrophil migration, including microfluidics and live imaging using mice and zebrafish. Neutrophil migration in response to injury or infection occurs in phases: early recruitment, amplification and resolution. Early-recruited neutrophils modulate the amplification phase both directly and indirectly through the activation of tissue and tissue-resident cells, producing sustained signals such as the CXC-chemokine ligand 8 family chemokines. Activated neutrophils at a site of inflammation do not necessarily undergo apoptosis but in some circumstances might undergo reverse migration away from the site of damage (reverse neutrophil migration) and/or re-enter the circulation (reverse transendothelial migration (rTEM)). Neutrophil forward and reverse migration may be attractive targets for anti-inflammatory therapies. Neutrophils follow a multitude of signals to reach sites of injury or infection. Understanding how this occurs and what the fate of these neutrophils is provides insight into how immune responses are controlled and chronic inflammation is avoided. In this Review, the authors describe the movement of neutrophils during inflammation. Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model systems have helped to uncover the behaviour of neutrophils in injured and infected tissues. Although neutrophils were considered to be short-lived effector cells that undergo apoptosis in damaged tissues, recent evidence suggests that neutrophil behaviour is more complex and, in some settings, neutrophils might leave sites of tissue injury and migrate back into the vasculature. The role of reverse migration and its contribution to resolution of inflammation remains unclear. In this Review, we discuss the different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection and the implications of these mechanisms to human disease.

IntroductionThe Interstitial Lung Diseases (ILD) are a heterogeneous group of inflammatory and fibrotic diseases of the interstitium, with worst cases resulting in pulmonary fibrosis (PF). Increased neutrophils are found within the lung or bronchoalveolar lavage (BAL) in ILD and predict a poor prognosis. Neutrophil adhesion molecules, e.g., CD18/b2 integrins (LFA-1; CD11a, Mac-1; CD11b and CR3; CD11c) and L-Selectin (CD62L) regulate cellular recruitment and fibrosis in animal models of bleomycin-induced PF. Expression of the Fc receptor (CD16) is upregulated during neutrophil activation, whilst ICAM-1 (CD54) is a marker for neutrophil reverse-transmigration back across the endothelium.Study AimInvestigate adhesion molecule expression profile of neutrophils in ILD patients compared to controls.MethodsBAL samples were collected from ILD and non-ILD patients undergoing bronchoscopy with informed consent. Adhesion molecule expression was studied via flow cytometry by staining cells with CD16, CD62L, CD11b, CD11c, CD11a, CD18 and CD54 antibodies.ResultsFlow cytometric analysis of BAL showed significantly more neutrophils in ILD lavage express CD11b and CD18 compared to non-ILD controls (p=0.0016 and p=0.0211 respectively). No significant differences were found in CD11c or CD11a expression. Further analysis revealed ILD lavage contained a higher percentage of CD16briCD62Ldim neutrophil subset expressing CD11b than non-ILD lavage controls (p<0.0001); a subset previously associated with a suppressive phenotype.1 In addition, ICAM-1 expression was significantly down-regulated in ILD lavage neutrophils (p=0.0397) and this was also reflected in the CD16briCD62Ldim neutrophil population (p=0.0445).ConclusionsFrom our preliminary study, we have observed an increased percentage of CD16briCD62LdimCD11b+ subset of neutrophils in ILD lavage compared to controls. ILD lavage neutrophils express significantly less ICAM-1. This suggests that more neutrophils are entering and being retained within the lung in ILD. Further experiments will dissect whether ILD neutrophils have altered functions (such as NETosis, ROS production, adhesion or migration) to contribute to disease progression.ReferencePillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW, et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest 2012;122(1):327–36.

The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery. The presence of several biological barriers impede the efficacy of nano-mediated drug delivery for solid cancer therapy. Here, the authors develop a nano-pathogenoid system that targets circulating neutrophils and show that it overcomes these biological barriers and improves tumour targeting and efficacy.

Abstract Neutrophil (PMN) migration across the intestinal mucosa correlates with disease flares in individuals with IBD. Despite this correlation, molecular events regulating PMN transepithelial migration (TEpM) are still elusive. However, it is clear that the leukocyte integrin CD11b/CD18 and the ubiquitously expressed membrane glycoprotein CD47 play crucial roles in this process. We hypothesized that CD47 interacts with CD11b/CD18 to regulate PMN trafficking in the gut. In vivo ileal loop assays showed reduced PMN migration into the lumen of CD47-/- mice in response to LTB4 (>60% reduction vs WT; p<0.05). This reduction is not due to the loss of CD47 on intestinal epithelial cells, as there were no differences in PMN migration between VillinCreCD47fl/fl mice and control CD47fl/fl mice. In vitro assays demonstrated a 25% reduction in LTB4 driven TEpM with CD47-/- PMN. In addition, blocking CD11b/CD18 antibody (mAb) reduced WT PMN migration to levels similar to those observed with CD47-/- PMN. However, CD11b/CD18 mAb did not reduce migration of CD47-/- PMN further, suggesting that CD47 plays a role in regulating integrin-dependent chemotaxis. In co-immunoprecipitation assays, CD47 was observed to associate with CD11b in PMN. Furthermore, we observed that upregulation of CD11b upon stimulation was reduced in CD47-/- PMN compared to WT, despite expression of similar levels at baseline. Consistent with these results, we observed reduced upregulation of CD11b upon chemoattractant stimulation in CD47 deficient human neutrophil like HL60 cells. Lastly, using antibodies specific for high affinity conformation of CD11b/CD18, we observed reduced CD11b/CD18 activation in CD47 deficient HL60 cells. These data support a role for CD47 in regulating PMN TEpM through effects on CD11b/CD18 functions. Targeting CD47 may provide a new therapeutic approach aimed at reducing pathologic intestinal inflammation in IBD.

The C-type lectin receptor–Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans . The cytokine IL-1β served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1β and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1β, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1β and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host–pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS. Innate immunity protects the central nervous system against fungal pathogens. Lionakis and colleagues identify Candidalysin, a Candida virulence factor that elicits microglial expression of the cytokine IL-1β and chemokine CXCL1 and facilitates neutrophil recruitment. Alteration of this pathway impairs antifungal responses.

Understanding the mechanism of protective immunity in the nasal mucosae is central to the design of more effective vaccines that prevent nasal infection and transmission of Bordetella pertussis. We found significant infiltration of IL-17-secreting CD4+ tissue-resident memory T (TRM) cells and Siglec-F+ neutrophils into the nasal tissue during primary infection with B. pertussis. Il17A−/− mice had significantly higher bacterial load in the nasal mucosae, associated with significantly reduced infiltration of Siglec-F+ neutrophils. Re-infected convalescent mice rapidly cleared B. pertussis from the nasal cavity and this was associated with local expansion of IL-17-producing CD4+ TRM cells. Depletion of CD4 T cells from the nasal tissue during primary infection or after re-challenge of convalescent mice significantly delayed clearance of bacteria from the nasal mucosae. Protection was lost in Il17A−/− mice and this was associated with significantly less infiltration of Siglec-F+ neutrophils and antimicrobial peptide (AMP) production. Finally, depletion of neutrophils reduced the clearance of B. pertussis following re-challenge of convalescent mice. Our findings demonstrate that IL-17 plays a critical role in natural and acquired immunity to B. pertussis in the nasal mucosae and this effect is mediated by mobilizing neutrophils, especially Siglec-F+ neutrophils, which have high neutrophil extracellular trap (NET) activity.