Neutrophils and COVID-19: The Road So Far

International Immunopharmacology 90 2021 107233 Available online 30 November 2020 15675769 2020 Elsevier BV All rights reserved Review Neutrophils and COVID19 The road so far Luiz Henrique Agra CavalcanteSilva Deyse Cristina Madruga Carvalho Essia de Almeida Lima Jose GFM Galvao Juliane S de França da Silva Jose Marreiro de SalesNeto Sandra RodriguesMascarenhas Laboratorio de Imunobiotecnologia Centro de Biotecnologia Universidade Federal da Paraíba UFPB Joao Pessoa Brazil A R T I C L E I N F O Keywords Inflammation Chemokines NETs SARSCoV2 A B S T R A C T The SARSCov2 infection triggers a multisystem inflammatory disorder knowing as COVID19 a pandemic disease This disease is characterized by acute respiratory distress syndrome cytokinedriven hyper inflammation and leukocytes count changes The innate immune response has been linked to COVID19 immunopathogenesis eg dysfunctional IFN response and myeloid inflammation In this regard neutrophils have been highlighted as essential effector cells in the development of COVID19 This review summarized the significant finds about neutrophils and its effector mechanisms eg neutrophils enzymes and cytokines neutrophil extracellular traps in COVID19 so far 1 Introduction COVID19 COVID19 Coronavirus disease 2019 is an infectious inflammatory disease caused by SARSCoV2 severe acute respiratory syndrome coronavirus 2 1 a new type of coronavirus identified in China in December 2019 after several patients were diagnosed with nonspecific pneumonia 2 The coronavirus outbreak began in Wuhan the capital of Hubei province and quickly spread across continental dimensions turning Covid19 into a pandemic disease 3 Coronaviruses are singlestranded RNA viruses that are character ized by having coronalike projections on their surface There are four main proteins in the structure of these microorganisms including the spike protein S which is related to the host cell mechanism of invasion 4 The SARSCoV2 is the third virus of the β coronavirus group to demonstrate the capacity to infect humans with pandemic potential 5 SARSCoV and the MERSCoV Middle Eastern respiratory syndrome coronavirus were responsible for previous relevant outbreaks of respi ratory disease in 2003 67 and 2012 89 respectively Humantohuman transmission occurs through direct contact or respiratory droplets from infected individuals whether symptomatic or asymptomatic 1012 Several reports have suggested that other forms of transmission such as the fecaloral route 1316 and intrauterine vertical transmission may also happen 1718 However more studies need to be carried out to confirm this form of transmission The clinical features of COVID19 may appear after an incubation period of around 514 days 19 Some early symptoms resemble those of other viral respiratory infections such as those caused by influenza viruses However dyspnea and high fever define the main clinical dif ference between COVID19 and common cold 20 Additionally when compared to the influenza virus SARSCoV2 infection presents greater chances of progressing to severe and critical infections which require oxygen therapy and ventilatory support 21 Elderly patients and those with chronic conditions have higher risks of rapid progression to acute respiratory distress syndrome ARDS and multiple organ failure often resulting in death These features demonstrate a systemic aspect of this infection which is accompanied by an intense inflammatory process 2224 2 COVID19 and inflammation The COVID19 infection starts by exposure to microdroplets present in the exhalations of infected individuals Then the SARSCoV2 spreads to the bronchioles and alveolar spaces 25 entrancing into the host cells eg endothelial epithelial and smooth muscle cells by binding the angiotensinconverting enzyme ACE2 a metallopeptidase present on the cell surface 2629 In the lung SARSCoV2 infects the alveolar cells type I and II pneumocytes and alveolar macrophages and then starts intracellular replication in pulmonary tissues Type I and III interferons IFN pro duction is an early defense mechanism in the alveolar cells 25 Corresponding author Email address sandracbiotecufpbbr S RodriguesMascarenhas Contents lists available at ScienceDirect International Immunopharmacology journal homepage wwwelseviercomlocateintimp httpsdoiorg101016jintimp2020107233 Received 17 September 2020 Received in revised form 13 November 2020 Accepted 22 November 2020 International Immunopharmacology 90 2021 107233 2 However recent researchers have found deficient expression of these cytokines besides the upregulated expression of chemokines and in terleukins 3031 In normal human bronchial epithelial NHBE cells culture the cytokine profile includes the IFNs deficiency and elevated expression of CCL20 CXCtype chemokines IL1β IL6 and tumor ne crosis factor TNF 31 The type I and III IFN absence shows that although SARSCoV2 is sensitive to IFN antiviral effect the virus can inhibit its induction 3134 This ability may come from at least one mechanism of blocking the activation of the IFN signaling pathway at an early step following the nuclear transport of interferon regulatory fac tors IRF 35 Furthermore the recruitment of leukocytes a hallmark of inflammation is strongly related to the chemokine profile For example CCL2 and CCL8 recruit monocytesmacrophages CXCL16 is a chemoattractant of NK cells CXCL8 is the principal neutrophil chemo attractant and CXCL9 and CXCL10 chemoattract T cells Thus the chemokine profile may be a driver of the signature pathology of SARS CoV2 36 The immune features between moderate and severe disease are modified after ten days of infection when severely ill patients remain with high proinflammatory cytokines 37 Furthermore deregulated inflammatory response to an infection may result in the cytokine storm syndrome which is associated with severe COVID19 3839 This syndrome is characterized by high levels of interleukins TNFα GCSF MCP1 and MIP1α which are higher in intensive care unit patients than nonintensive care unit patients 374041 Additionally the inflammasome NLRP3 a multiprotein complex crucial to the host de fense is highly activated in COVID19 patients Inflammasomeinduced cytokines IL1β and IL18 also contribute to cytokine storm and sus tained NLRP3 inflammasome activation is directly associated with the diseases severity 4244 The cytokines milieu recruits immune cells and activate T helper type 1 Th1 response which is related to the activation of a specific immune response Moreover Th1 cells stimulate IL6 production by inflammatory monocytes in severe COVID19 and contribute to the cytokine storm 45 However Th2 cytokines are also presented in COVID19 serum patients and may impair the Th1 inflammatory response 40 Thereby chemokinescytokines milieu comprises a possible therapeutic target for COVID19 46 Peripheral blood immune cells PBMCs of COVID19 patients pre sent low T cell number and frequency in both CD4 and CD8 pop ulations which are more activated On the order hand monocytes are increased but they present a reduction in HLADR expression compared with the control group noninfected 37 Additionally in severe COVID19 patients present a reduced number of B cells and natural killer NK cells associated with severe T cell depletion and a high neutrophil population 37404749 This neutrophilia occurs after seven days symptoms onset 50 3 Neutrophils in COVID19 Neutrophils are the most abundant immune cells in human blood They account for approximately 5070 of all leukocytes Besides serving as first responders to many infections neutrophils have critical homeostatic functions being also implicated in chronic inflammatory diseases 51 These polymorphonuclear cells play a protective role during bacterial or fungal infections however their role in viral in fections is not fully understood 5253 Although the evidence is limited it has been suggested that neutrophils enhance antiviral de fenses by interaction with other immune cell populations virus inter nalization and killing mechanism cytokines release degranulation oxidative burst and neutrophil extracellular traps NETs 5354 Neutrophils are present in many lung diseases associated with ARDS as reported in infections by influenza virus and SARSCoV1 55 A bioinformatic study presented data indicating that neutrophil activation and degranulation are highly activated processes in the SARS infection 56 Recently the recruitment of this polymorphonuclear PMN was observed in the immune response triggered by SARSCoV2 Furthermore neutrophilia has been described as an indicator of severe respiratory symptoms and a poor outcome in patients with COVID19 5759 Several studies have reported that neutrophiltolymphocyte ratio NLR a clinical inflammation biomarker is increased and predicts se vere illness in the early stage of SARSCoV2 infection 5962 Higher Ddimer and Creactive protein CRP levels follow NLRs increase in these patients 6364 Also increased NLR has been considered an in dependent risk factor for mortality in hospitalized patients 416566 related to some comorbidities eg diabetes and cardiovascular disease 67 A study observed that COVID19 diabetes patients with higher NLR had heavier severity and more extended hospital stay 68 This fact supports the idea that preexisting chronic inflammation contributes to COVID19 severity 6569 In addition to the NLR neutrophil to CD4 lymphocyte ratio NCD4LR has been associated with the negative conversion time NCT of SARSCoV2 A study found that high NCD4LR indicates worse im mune function and prolonged virus clearance 70 Another biomarker involving this PMN the neutrophil count to albumin ratio NAR has been described as a new predictor of mortality in COVID19 patients 71 Therefore the NCD4LR and NAR values also could be used as clinical markers for COVID19 progression in addition to the NLR 41 Besides the increase of neutrophils is not reported only in the bloodstream but also in the lungs 72 PMN infiltration in pulmonary capillaries with extravasation to alveolar space and neutrophilic mucositis was observed in lung autopsies obtained from patients who died from COVID19 indicating inflammation in the entire lower res piratory tract 7374 Moreover immature phenotype andor dysfunctional mature neutrophils have been described in severe COVID 19 patients 7576 These studies indicate that the increased infiltration of immature andor dysfunctional neutrophil contributes to the imbal ance of the lungs immune response in severe cases Respiratory epithelium infection by SARSCoV2 leads to cell secre tion of multiple cytokines chemokines and DAMPs as previously described 3177 Transcriptional analysis of bronchoalveolar lavage fluid BALF from COVID19 patients reported high levels of CXCL2 and CXCL8 chemokines that facilitate the PMN recruitment to the site of infection 7882 Although the neutrophils could present a protective role extensive and prolonged activation of these leukocytes can lead to detrimental effects in the lungs and result in pneumonia andor ARDS 8384 Wang and colleagues 50 also demonstrated that neutrophilia coincides with lung injury in severe COVID19 patients It has been described that neutrophils play a pivotal role in the development of ARDS caused by influenza infection 55 In COVID19 neutrophils accumulation generates toxic molecules that might contribute to ARDSs physiopathology 85 Respiratory burst from activated neutrophils induces ROS release such as superoxide radicals and H2O2 leading to oxidative stress that contributes to the cytokine storm and blood clots formation in SARSCoV2 infection 8687 Moreover decreased expression of the antioxidant enzyme superoxide dismutase 3 SOD3 in the lung tissue of old patients with COVID19 was also reported 88 Therefore excessive oxidative stress induced by PMN infiltration is related to the alveolar damage thrombosis and severity in COVID19 87 In addition to ROS formation neutrophil elastase has been implicated in COVID19 pathogenesis 8991 This proteolytic enzyme which is stored in azurophil granules is secreted to degrade antigens Nevertheless an imbalance of the elastase and other proteinases induces damage in the alveolarcapillary barrier resulting in tissue injury and edema formation 92 Furthermore persistently activated neutrophils contribute to main taining the inflammatory state in the lungs by cytokine release as observed in MERS and SARSCoV1 infections 93 Similar findings were described in SARSCoV2 infection by Parackova and colleagues 76 that reported the neutrophils as drivers of hyperinflammation by enhanced degranulation of primary granules and proinflammatory cy tokines release Taken together these molecules secreted by PMN can LHA CavalcanteSilva et al International Immunopharmacology 90 2021 107233 3 cause severe damage in alveolar tissue independently of the virus cytopathic effect Additionally Meizlish and colleagues 94 identified neutrophil ac tivators IL8 and GCSF and effectors resistin lipocalin2 and hepa tocyte growth factor as early biomarkers of severe COVID19 patients The authors also demonstrated a positive association between high levels in immature granulocytes and neutrophil counts with increased mortality 94 These data highlight the neutrophil role in the severity of COVID19 disease Viral infection can also induce the release of neutrophils extracel lular traps NETs by neutrophils 95 The NETs mechanism was first described by Brinkmann and colleagues in 2004 96 These traps consist of chromatin fibers associated with enzymes such as neutrophil elastase cathepsin G and myeloperoxidase 9798 NETs are known to immobilize and degrade bacteria fungi viruses being a critical effector mechanism to contain infections 99 However NETs can act as a doubleedged sword of immunity 98 having a pro or anti inflammatory effect 100101 Schauer and colleagues 102 reported that an aggregate of NETs can degrade cytokines and chemokines reducing inflammation This antiinflammatory effect has also been demonstrated in the ocular microenvironment 103 On the other hand NETs can promote tissue damage having already been shown that NETs and platelets interaction can cause endothelial damage in infections by Escherichia coli 104 NETs can also participate in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus and rheu matoid arthritis where elevated levels of NETs have been seen in serum and synovial fluid respectively in patients with these diseases 105106 Studies have been reported an elevated level of NETs in patients with COVID19 107109 and an increased plasma NETs is correlated with increased COVID19 severity 109 besides contributing to lung injury and microvascular thrombosis 107 The vascular occlusion caused by NETs is not only reported in lung tissue 110 but also in kidney and liver 111 which suggests that NETs thrombotic effects may be related to systemic and harmful effects of COVID19 This relationship between NETs and thrombosis may also be related to complement system acti vation Indeed C3 112 and C5 113 inhibition dampen NET release in COVID19 patients Since coagulation disorders are a worse prognosis to COVID19 114116 and both NETs and complement proteins are associated with these thrombotic events 113 therapies that focus on this triple complementNETscoagulation axis may be a therapeutic opportunity At the transcriptional level Wang and collaborators 50 demon strated activation of several NETsassociated in COVID19 patients They hypothesized that some of them could be related to negative regulation of NK and T cell dampening antiviral response 50 In severe COVID19 Veras and colleagues 109 demonstrated that neutrophils both circulating and lunginfiltrating release high levels of NETs The authors also present data that demonstrate a NETs release directly induced by SARSCoV2 117 This SARSCoV2induced NETs release is PAD4dependent 109 PAD4 is critical to NET formation because it promotes a process of hypercitrulination of histones resulting in chro matin decondensation 118 The SARSCoV2activated neutrophils can also induce apoptosis in lung epithelial A549 cells reinforcing neutrophil role in COVID19 immunopathology and other coronavirus infections 109 4 Conclusions The literature related to neutrophil and COVID19 so far demon strated a crucial role of these polymorphonuclear cells in the patho genesis of COVID19 Fig 1 Despite the immune system modulation needs being tightly controlled to avoid immunosuppression the different neutrophil mechanisms eg neutrophils enzymes and cyto kines NETs are potential targets to treat COVID19 mainly the severe cases Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper Fig 1 The neutrophil role in the lung tissue during infection by SARSCoV2 1 The neutrophiltolymphocyte ratio NLR is elevated in the bloodstream 2 The migrated neutrophils contribute to storm cytokines formation and release other mediators eg elastase neutro philic 3 SARSCoV2 infection pro motes neutrophil extracellular traps release which can contribute to lung damage and 4 immunothrombosis These many steps may be potential therapeutic targets Several other cells and mediators are involved in COVID19 immunopathology but they are sup pressed in this figure to highlight the neutrophil role The figure was created with BioRendercom 119 LHA CavalcanteSilva et al International Immunopharmacology 90 2021 107233 4 Acknowledgments We are grateful to CAPES PROCAD and CNPq Conselho Nacional de Desenvolvimento Científico e Tecnologico to fellowships support 15480120194 and 14130420170 References 1 MZ Tay CM Poh L Renia PA MacAry LFP Ng The trinity of COVID19 immunity inflammation and intervention Nat Rev Immunol 20 2020 363374 httpsdoiorg101038s4157702003118 2 N Zhu D Zhang W 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