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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.

Patients with antineutrophil cytoplasm antibody–associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53–1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40–1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

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.

Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.

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.

In this randomized trial involving patients with noncystic fibrosis bronchiectasis, the rate of pulmonary exacerbations over a 52-week period was lower with brensocatib (10 mg or 25 mg per day) than with placebo.

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.

Neutrophils have been classically viewed as a homogenous population. Recently, neutrophils were phenotypically classified into pro-inflammatory N1 and anti-inflammatory N2 sub-populations, but the functional differences between the two subtypes are not completely understood. We aimed to investigate the phenotypic and functional differences between N1 and N2 neutrophils, and to identify the potential contribution of the S100A9 alarmin in neutrophil polarization. We describe distinct transcriptomic profiles and functional differences between N1 and N2 neutrophils. Compared to N2, the N1 neutrophils exhibited: i) higher levels of ROS and oxidative burst, ii) increased activity of MPO and MMP-9, and iii) enhanced chemotactic response. N1 neutrophils were also characterized by elevated expression of NADPH oxidase subunits, as well as activation of the signaling molecules ERK and the p65 subunit of NF-kB. Moreover, we found that the S100A9 alarmin promotes the chemotactic and enzymatic activity of N1 neutrophils. S100A9 inhibition with a specific small-molecule blocker, reduced CCL2, CCL3 and CCL5 chemokine expression and decreased MPO and MMP-9 activity, by interfering with the NF-kB signaling pathway. Together, these findings reveal that N1 neutrophils are pro-inflammatory effectors of the innate immune response. Pharmacological blockade of S100A9 dampens the function of the pro-inflammatory N1 phenotype, promoting the alarmin as a novel target for therapeutic intervention in inflammatory diseases.