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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.

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.

PurposeAdmission Neutrophil-lymphocyte ratios (NLR) is significantly correlated with 90 days functional outcome in acute ischemic strokes. The aim of our study was to detect post thrombectomy changes in NLR over 1 week with various degrees of revascularization and identify a relationship between NLR changes and 90-day functional outcome.MethodsWe retrospectively reviewed our prospective stroke database from Nov 2016 to May 2018 for patients who underwent endovascular thrombectomy for anterior circulation large vessel occlusions with an admission NLR (NLR 1) and 72 hours follow-up NLR (NLR 2). We measured stroke severity by NIHSS, degree of recanalization by modified Thrombolysis in Cerebral Infarction (mTICI) score, and clinical outcomes by the modified Rankin Scale (mRS) at 3 months. Univariate analysis was conducted between age, NLR1, NLR2, change in NLR (NLR2-NLR1), NIHSS, mTICI and mRS using correlation coefficient. Change in mean NLR was assessed using Wilcoxon rank sum test. Multivariable logistic regression models were developed to identify effect of NLR 2 on favorable functional outcome (mRS≤2) while controlling for age, NIHSS and IV rtPA utilization.Results88 patients met our inclusion criteria with a median NIHSS at admission of 18 (4–32), and 90 days mRS of 3 (0–6). An increase in NLR was identified in 75% of patients following endovascular thrombectomy. Mean NLR 2 was significantly higher than NLR 1 (5.5 vs 3.1, p<0.001). There was a significantly negative correlation between TICI and change in NLR (p=0.002), and a significantly positive correlation between change in TICI and 90-day mRS (p=0.034), as well as NLR2 and mRS (p<0.001). No correlation was observed between NLR1 and mRS (p=0.22). High NLR2 was an independent predictor of poor functional outcome (OR=1.34, p=0.002).ConclusionNLR is a readily available biomarker that correlates with degrees of revascularization post-thrombectomy. Improved recanalization and reperfusion is associated with lower follow-up NLR at 72 hours and follow up NLR is an independent predictor of functional outcome.Disclosures R. Abdalla: None. M. Darwish: None. M. Aly: None. M. Potts: None. B. Jahromi: None. A. Shaibani: None. M. Hurley: None. S. Ansari: None.

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.

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 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.

Of all cells implicated in the pathology of rheumatoid arthritis (RA), neutrophils possess the greatest cytotoxic potential, owing to their ability to release degradative enzymes and reactive oxygen species. Neutrophils also contribute to the cytokine and chemokine cascades that accompany inflammation, and regulate immune responses via cell-cell interactions. Emerging evidence suggests that neutrophils also have a previously unrecognised role in autoimmune diseases: neutrophils can release neutrophil extracellular traps (NETs) containing chromatin associated with granule enzymes, which not only kill extracellular microorganisms but also provide a source of autoantigens. For example, citrullinated proteins that can act as neoepitopes in loss of immune tolerance are generated by peptidylarginine deiminases, which replace arginine with citrulline residues, within neutrophils. Indeed, antibodies to citrullinated proteins can be detected before the onset of symptoms in patients with RA, and are predictive of erosive disease. Neutrophils from patients with RA have an increased tendency to form NETs containing citrullinated proteins, and sera from such patients contain autoantibodies that recognize these proteins. Thus, in addition to their cytotoxic and immunoregulatory role in RA, neutrophils may be a source of the autoantigens that drive the autoimmune processes underlying this disease.

Ischemia-reperfusion injury (IRI) is the main cause of morbidity and mortality due to graft rejection after liver transplantation. During IRI, an intense inflammatory process occurs in the liver. This hepatic inflammation is initiated by the ischemic period but occurs mainly during the reperfusion phase, and is characterized by a large neutrophil recruitment to the liver. Production of cytokines, chemokines, and danger signals results in activation of resident hepatocytes, leukocytes, and Kupffer cells. The role of neutrophils as the main amplifiers of liver injury in IRI has been recognized in many publications. Several studies have shown that elimination of excessive neutrophils or inhibition of their function leads to reduction of liver injury and inflammation. However, the mechanisms involved in neutrophil recruitment during liver IRI are not well known. In addition, the molecules necessary for this type of migration are poorly defined, as the liver presents an atypical sinusoidal vasculature in which the classical leukocyte migration paradigm only partially applies. This review summarizes recent advances in neutrophil-mediated liver damage, and its application to liver IRI. Basic mechanisms of activation of neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of danger signals, adhesion molecules, chemokines, glycosaminoglycans (GAGs), and metalloproteinases is explored. The precise definition of the molecular events that govern the recruitment of neutrophils and their movement into inflamed tissue may offer new therapeutic alternatives for hepatic injury by IRI and other inflammatory diseases of the liver.

New evidence has challenged the outdated dogma that neutrophils are a homogeneous population of short-lived cells. Although neutrophil subpopulations with distinct functions have been reported under homeostatic and pathological conditions, a full understanding of neutrophil heterogeneity and plasticity is currently lacking. We review here current knowledge of neutrophil heterogeneity and diversity, highlighting the need for deep genomic, phenotypic, and functional profiling of the identified neutrophil subpopulations to determine whether these cells truly represent bona fide novel neutrophil subsets. We suggest that progress in understanding neutrophil heterogeneity will allow the identification of clinically relevant neutrophil subpopulations that may be used in the diagnosis of specific diseases and lead to the development of new therapeutic approaches.