Cited by 571Chemokine receptors and signalingNeutrophil, Myeloperoxidase and Oxidative MechanismsInflammation biomarkers and pathways

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Neutrophil chemoattractant receptors in health and disease: double-edged swords

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Metzemaekers, Mieke, Gouwy, Mieke, Proost, Paul·2020·Cellular & Molecular Immunology

DOI 10.1038/s41423-020-0412-0PMC PMC7192912

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Abstract

Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high cytotoxic potential. Accurate neutrophil recruitment is essential to combat microbes and to restore homeostasis, for inflammation modulation and resolution, wound healing and tissue repair. After fulfilling the appropriate effector functions, however, dampening neutrophil activation and infiltration is crucial to prevent damage to the host. In humans, chemoattractant molecules can be categorized into four biochemical families, i.e., chemotactic lipids, formyl peptides, complement anaphylatoxins and chemokines. They are critically involved in the tight regulation of neutrophil bone marrow storage and egress and in spatial and temporal neutrophil trafficking between organs. Chemoattractants function by activating dedicated heptahelical G protein-coupled receptors (GPCRs). In addition, emerging evidence suggests an important role for atypical chemoattractant receptors (ACKRs) that do not couple to G proteins in fine-tuning neutrophil migratory and functional responses. The expression levels of chemoattractant receptors are dependent on the level of neutrophil maturation and state of activation, with a pivotal modulatory role for the (inflammatory) environment. Here, we provide an overview of chemoattractant receptors expressed by neutrophils in health and disease. Depending on the (patho)physiological context, specific chemoattractant receptors may be up- or downregulated on distinct neutrophil subsets with beneficial or detrimental consequences, thus opening new windows for the identification of disease biomarkers and potential drug targets.

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D’Agnillo, F., Zhang, X., & Williams, M. C. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.06.007 · Cited by 8
RNA-seq analysis reveals modulation of inflammatory pathways by an enriched-triterpene natural extract in mouse and human macrophage cell lines
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“NFKBIZ, a member of the ankyrin-repeat family and induced by lipopolysaccharide (LPS), OSM, a member of the IL-6 family of cytokines, and GBP5, a member of the dynamin superfamily of GTPases, are involved in the induction of inflammatory genes, including IL6 and IL1A [43 – 46].”
Background
LTB4 is converted into a potent human neutrophil NADPH oxidase activator via a receptor transactivation mechanism in which the BLT1 receptor activates the free fatty acid receptor 2
Wu, Y., Dahlgren, C., Forsman, H. F., & Sundqvist, M. (2025) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2025.102680 · Cited by 7
Serum amyloid A: multifaceted roles in inflammation and cellular interactions
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“DCs serve as critical antigen-presenting cells bridging innate and adaptive immunity [141].”
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Lemus‐Conejo, A., Medrano, M., López, S., Millán-Linares, M. C., Rosillo, M. Á., Pérez‐Simón, J. A., Muriana, F. J. G., & Abia, R. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202001203 · Cited by 9
Sentinel Lymph Node Gene Expression Signature Predicts Recurrence-Free Survival in Cutaneous Melanoma
Karapetyan, L., Gooding, W. E., Li, A., Yang, X., Knight, A., Abushukair, H. M., Stefano, D. V. D., Sander, C., Karunamurthy, A. D., Panelli, M. C., et al. (2022) · Cancers · doi:10.3390/cancers14204973 · Cited by 7
“Neutrophils have been shown to suppress tumor metastasis [48,49] and inflammatory (C-X-C) chemokines have been shown to recruit effector cells to the tumor site.”
Background
The Olfactomedin-4-Defined Human Neutrophil Subsets Differ in Proteomic Profile in Healthy Individuals and Patients with Septic Shock
Lundquist, H., Andersson, H., Chew, M. S., Das, J., Turkina, M. V., & Welin, A. (2022) · Journal of Innate Immunity · doi:10.1159/000527649 · Cited by 8
“…[28], Rab3a, suggested to be involved in neutrophil degranulation [29], CXCR1, a major neutrophil chemotactic receptor that binds interleukin-8 [30], and neutrophil defensin alpha 4, an antimicrobial peptide with bactericidal activity [31], showed higher abundance in the Olfm4-L neutrophils.”
Background
Increased neutrophil derived chemokines (CXCL10 and CCL2) in human trichinellosis as possible serological markers of the polarization of the immune response against the parasite
Bruschi, F., Pinto, B., Fallahi, P., Ferrari, S. M., & Antonelli, A. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156205 · Cited by 7
Loss of adenosine A3 receptors accelerates skeletal muscle regeneration in mice following cardiotoxin-induced injury
Tarban, N., Papp, A. B., Deák, D., Szentesi, P., Halász, H., Patsalos, A., Csernoch, L. J., Sarang, Z., & Szondy, Z. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06228-7 · Cited by 7
“To test whether loss of A3Rs affects transmigration of in ﬂ ammatory cells if they are lost separately in the bone marrow-derived or in the tissue-resident cells, the transmigration of CD45 + leukocytes was also determined in the above setup two days following CTX-induced injury (Fig.”
Whole blood transcriptomics reveals granulocyte colony‐stimulating factor as a mediator of cardiopulmonary bypass‐induced systemic inflammatory response syndrome
Martin, K., Gamell, C., Tai, T. Y., Bonelli, R., Hansen, J. A., Tatoulis, J., Alhamdoosh, M., Wilson, N. J., & Wicks, I. P. (2024) · Clinical & Translational Immunology · doi:10.1002/cti2.1490 · Cited by 7
“33,34 Inhibitors to CXCR1 and 2 are effective in controlling neutrophil-mediated inﬂammation in various animal models of disease.”
Background
Dissecting thrombus-directed chemotaxis and random movement in neutrophil near-thrombus motion in flow chambers
Korobkin, J.-J. D., Деордиева, Е. А., Tesakov, I. P., Adamanskaya, E.-I. A., Boldova, A. E., Boldyreva, A. A., Galkina, S. V., Lazutova, D. P., Martyanov, A. A., Pustovalov, V., et al. (2024) · BMC Biology · doi:10.1186/s12915-024-01912-2 · Cited by 7
“Granulocyte chemotaxis plays a crucial role in various physiological processes such as immune responses, tumor metastasis, wound healing, and the formation of blood vessels [55].”
Background
The impact of the tumor microenvironment on the survival of penile cancer patients
Lohse, S., Mink, J. N., Eckhart, L., Hans, M. C., Jusufi, L., Zwick, A., Mohr, T., Bley, I. A., Khalmurzaev, O., Matveev, V. B., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-70855-z · Cited by 7
“…neutrophils in the tumor core of head and neck cancer 17 as strongly associated with metastases, advanced-stage disease, inferior OS and disease-free survival 2,22,23,27–31, 37, 38 and PeCa present as histological and pathogenetic different HPV-related and non-related subtypes 10–13 , 40 .”
Background
Mouse lemur cell atlas informs primate genes, physiology and disease
Ezran, C., Liu, S., Chang, S., Ming, J., Guethlein, L. A., Wang, M. F. Z., Dehghannasiri, R., Olivieri, J. E., Frank, H. K., Tarashansky, A. J., et al. (2025) · Nature · doi:10.1038/s41586-025-09114-8 · Cited by 17
“…markers that facilitate extravasation, induction of chemokines that promote homing to inflammatory sites and recruitment of additional neutrophils ( CXCL8 (also known as IL8 ) and CCL5 (also known as RANTES )) 31 and markers of neutrophil ageing and lymph node trafficking (Extended Data Fig.”
Protein based nanomedicine: Promising therapeutic modalities against inflammatory disorders
Zaheer, Y., Vorup‐Jensen, T., Webster, T. J., Ahmed, M., Khan, W. S., & Ihsan, A. (2021) · Nano Select · doi:10.1002/nano.202100214 · Cited by 7
An increase in the cytosolic concentration of free calcium ions activates the neutrophil NADPH-oxidase provided that the free fatty acid receptor 2 has been allosterically modulated
Lind, S., Wu, Y., Sundqvist, M., Forsman, H. F., & Dahlgren, C. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110687 · Cited by 7
Sex disparities in non-small cell lung cancer: mechanistic insights from a cRaf transgenic disease model
Zhong, S., & Borlak, J. T. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104763 · Cited by 6
Exploring the molecular mechanism of estrogen therapy effectiveness after TCRA in IUA patients at single-cell level
Du, Y., Shuai, R., Luo, S., Jin, Y., Xu, F., Zhang, J., Liu, D., & Feng, L. (2024) · Biology Direct · doi:10.1186/s13062-024-00583-x · Cited by 8
Inflammatory changes in the choroid plexus following subarachnoid hemorrhage: the role of innate immune receptors and inflammatory molecules
Solar, P., Brázda, V., Bareš, M., Zamani, A., EmamiAref, P., Joukal, A., Kubíčková, L., Kročka, E., Hašanová, K., & Joukal, M. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1525415 · Cited by 6
Mineralocorticoid receptor antagonism improves corneal integrity in a rat model of limbal stem cell deficiency
Rodrigues‐Braz, D., Bonnet, C., Zhu, L., Yeşilırmak, N., Gélizé, E., Jonet, L., Jaisser, F., Bourges, J., Béhar‐Cohen, F., & Zhao, M. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117979 · Cited by 6
PRIM1 enhances colorectal cancer liver metastasis via promoting neutrophil recruitment and formation of neutrophil extracellular trap
Ju, W., Song, J., Ge, Y., Hou, S., Chang, Y., Chen, X., Nie, Z., Guo, L., & Yin, J. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.111822 · Cited by 6
Dynamic immunomodulatory nanoarchitectonics: Rewiring tissue regenerative microenvironment via intelligent regulation
Yuan, H., Li, B., Shao, X., Xi, Y., Cheng, S., Liu, A., & Zheng, B. (2025) · Nano Research · doi:10.26599/nr.2025.94907777 · Cited by 7
Platelet‐Activating Factor Promotes Neutrophil Activation and Platelet–Neutrophil Complex Formation
Wohlgemuth, L., Knapp, C. L., Vidoni, L., Hug, S., Müller, P. F., Mohamed, A. O. K., Dietz, A., Stratmann, A. E. P., Stukan, L., Höpfer, L. M., et al. (2025) · Scandinavian Journal of Immunology · doi:10.1111/sji.70044 · Cited by 6
“…activating neutrophils via binding to specific G-protein coupled receptors, including the chemotactic lipid LTB 4 known as an intermediate target chemokine and end-target formyl peptides including fMLF [28], as well as the cytokine TNF known as quite persuasive agent for neutrophil function [49].”
Epigenetic Regulation of Neutrophils in ARDS
Williams, J. E., Mauya, Z., Walkup, V., Adderley, S., Evans, C. E., & Wilson, K. M. (2025) · Cells · doi:10.3390/cells14151151 · Cited by 6
The role of neutrophil-related indicators in aneurysmal subarachnoid hemorrhage
Tian, Q., Yan, Z., Cheng, J., Li, Z., Jiang, S., Zhao, X., Zhang, G., Chen, Z., & Li, M. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107062 · Cited by 6
Integrative analysis of network pharmacology and proteomics reveal the protective effect of Xiaoqinglong Decotion on neutrophilic asthma
Liao, G., Yan, Q., Zhang, M., Zhang, X., Yang, J., Huang, H.-T., Liu, X., Jiang, Y., Gong, J., Zhan, S., et al. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118102 · Cited by 7
Neutrophils in toxicology: a forgotten field
Scharf, P. R. D. S., Aschner, M., & Farsky, S. H. P. (2024) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2024.2431692 · Cited by 6
“In this context, C-X-C motif chemokine ligand 8 (CXCL8), leukotriene B4 (LTB4), the C5 activated fraction of complement (C5a), and formyl peptides of membrane bacteria (fMLP) bind to GPCRs and downstream intracellular pathways involved in neutrophil chemotaxis (Metzemaekers, Gouwy, and Proost 2020).”
Snowflake‐Like RuMn Branched Nanosheets Enable Topocatalytic Therapy of Cardiac Ischemia/Reperfusion Injury via Resisting Inflammatory Cascade and Neutrophil Invasion
Mo, X., Liu, L., Zhang, L., Hu, M., Xiang, H., Chen, Y., & Zhang, B. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202415084 · Cited by 6
Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice
Panja, S., Benjamin, J. T., & Paria, B. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157932 · Cited by 5
“Chemokines including C-X-C motif chemokine ligand 1 (Cxcl1) and C-X-C motif chemokine ligand 2 (Cxcl2) are considered as strong chemoattractants for NPs [12].”
Background
Potential targets of phytochemical immunomodulatory therapy in periodontitis immunopathogenesis: A narrative review
Sarasati, A., & Jonarta, A. L. (2023) · The Saudi Dental Journal · doi:10.1016/j.sdentj.2023.08.005 · Cited by 6
“Neutrophil recruitment, migration, and inﬁltration are accelerated in patients with periodontitis, while phagocytic activity is signiﬁcantly diminished (Hajishengallis, 2020; Metzemaekers et al., 2020; Sell et al., 2017; Yang et al., 2021).”
Background
Pre-Activated Granulocytes from an Autoimmune Uveitis Model Show Divergent Pathway Activation Profiles upon IL8 Stimulation In Vitro
Hoffmann, A. L. C., Hauck, S. M., Deeg, C. A., & Degroote, R. L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179555 · Cited by 6
“Unlike the other two stimulants used, namely phorbol 12-myristate 13-acetate (PMA), which mainly induces exocytosis, ROS release and NET formation via protein-kinase-C [30], and lipopolysaccharide (LPS), which triggers similar responses by binding to TLR4 on neutrophils [31], IL8 has s been proven to be a strong and s…”
Background
Constitutive immune surveillance of nasal mucosa by three neutrophil subsets with distinct origin, phenotype, and functionPreprint
Gonzalez, R. J., Hanč, P., Álvarez, D., Kazer, S. W., Messou, M.-A., Mazo, I. B., Matysiak, C., Garg, R., Helble, J. D., Pallis, P., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.06.583781 · Cited by 7
Cellular dynamics of cervical remodelling: insights from preterm and term labour
de Almeida, J. P. R. F. P., Matias, A., & Bartosch, C. (2025) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-024-07902-7 · Cited by 5
“In contrast, preterm cervical remodelling involves significant participation of inflammatory cells and markers [29–38].”
Single-cell analysis of human airway epithelium identifies cell-type-specific responses to Aspergillus and Coccidioides
Harding, A. T., Crossen, A. J., Reedy, J. L., Basham, K. J., Hepworth, O. W., Zhang, Y., Shah, V. S., Brown, H. E., Surve, M. V., Simaku, P., et al. (2025) · mBio · doi:10.1128/mbio.02121-25 · Cited by 5
“Chemokines, including CXCL8, CCL20, and MIF, recruit immune cells, such as neutrophils, macrophages, and T cells, to sites of infection and inflammation and play critical roles in the immune response to pathogens (45–48).”
Integration of single-cell RNA sequencing and spatial transcriptomics reveals neutrophil diversity and spatial heterogeneity in acute kidney injury
Liu, X., Li, Z., Mao, L., Lü, Y., Li, C., Xin, X., Jiang, L., Wang, Z., Sun, P., Xu, L., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.148478 · Cited by 5
The Paradox of NET Involvement in the Pathogenesis of Inflammatory Bowel Disease
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Neutrophils: emerging perspectives on the pathogenesis of oral mucosal diseases
Chen, Y., Mi, Q., Jia, F., & Meng, W. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1689266 · Cited by 7
“On one hand, the excessive or sustained activation of neutrophils, although intended to eliminate pathogens, also leads to collateral damage to host tissues due to the release of large amounts of proteases, reactive oxygen species, and other substances (Metzemaekers et al., 2020).”
DUOX2 regulates secreted factors in virus‐infected respiratory epithelial cells that contribute to neutrophil attraction and activation
Kasumba, D. M., Huot, S., Caron, E., Fortin, A., Laflamme, C., Cuervo, N. Z., Lamontagne, F., Pouliot, M., & Grandvaux, N. (2023) · The FASEB Journal · doi:10.1096/fj.202201205r · Cited by 5
Impact of endoplasmic reticulum aminopeptidases 1 (ERAP1) and 2 (ERAP2) on neutrophil cellular functions
Saulle, I., Limanaqi, F., Garziano, M., Murno, M. L., Artusa, V., Strizzi, S., Giovarelli, M., Schulte, C., Aiello, J., Clerici, M., et al. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1506216 · Cited by 5
“The driving factor in this process is probably represented by IL-8, which is known to be a chemotactic determinant for neutrophils (Metzemaekers et al., 2020).”
Pathogenic and Protective Roles of Neutrophils in Chlamydia trachomatis Infection
Wilton, Z. E. R., Jamus, A. N., Core, S. B., & Frietze, K. M. (2025) · Pathogens · doi:10.3390/pathogens14020112 · Cited by 6
“It is important to note that knocking out CXCR2 could impact other cell types, such as monocytes, that express this chemokine receptor [64].”
CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity
Pun, N., Cytlak, U., Lee, D. C. H., Domingues, R. G., Cheadle, E. J., Forster, D. M., Whiteley, C. H., Honeychurch, J., Williams, K. J., Graham, G. J., et al. (2025) · Mucosal Immunology · doi:10.1016/j.mucimm.2025.10.008 · Cited by 5
Bacteriophage: A new therapeutic player to combat neutrophilic inflammation in chronic airway diseases
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Spatial distribution-based progression of spinal cord injury pathology: a key role for neuroimmune cells
Li, J., Zhai, X.-L., & Yu, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1505755 · Cited by 5
Associations between Circulating VEGFR2hi-Neutrophils and Carotid Plaque Burden in Patients Aged 40-64 without Established Atherosclerotic Cardiovascular Disease
Genkel, V. V., Dolgushin, I. I., Baturina, I., Savochkina, A. Y., Никушкина, К. В., Minasova, A. A., Kuznetsova, A., & Иосифович, Ш. И. (2022) · Journal of Immunology Research · doi:10.1155/2022/1539935 · Cited by 5
“We think that this could be because in conditions of extent atherosclerosis and systemic vascular remodeling, there can be an increased migration of VEGFR2 hi -neutrophils into the tissue (mediated by both VEGFR and CXCR2), which leads to a decrease in their number in the systemic circulation [28].”
Endogenous Retroviruses Augment Amphibian (Xenopus laevis) Tadpole Antiviral Protection
Kalia, N., Hauser, K. A., Burton, S., Hossainey, M. R. H., Zelle, M., Horb, M. E., & Grayfer, L. (2022) · Journal of Virology · doi:10.1128/jvi.00634-22 · Cited by 5
“cells, such as granulocytes (30), amphibian tadpoles do not begin to form bone mar-”
Background
Heterodimerization of Chemoreceptors TAS1R3 and mGlu2 in Human Blood Leukocytes
Ball, L., Bauer, J., & Krautwurst, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612942 · Cited by 6
Delayed CCL23 response is associated with poor outcomes after cardiac arrest
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Investigating pulmonary neutrophil responses to inflammation in mice via flow cytometry
Song, Z., Clemens, R. A., Zhang, Y., Chen, J., Wang, Y., Dinauer, M. C., & Meng, S. (2024) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiae189 · Cited by 4
A vasculature-resident innate lymphoid cell population in mouse lungs
Shirley, S., Ichise, H., Natale, V. D., Jin, J., Wu, C. C., Zou, R., Zhang, W., Fang, Y., Zhang, Y., Chen, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58982-1 · Cited by 6
Oat Avenanthramide‐C Alleviates DSS‐Induced Colitis Through Regulating Intestinal Immune Activity and Gut Microbiota in Mice
Ye, G., Li, G., Wang, Z., Wang, Z., Wang, J., & Liu, J. (2025) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.70250 · Cited by 6

Authors: Metzemaekers, M., Gouwy, M., & Proost, P.
Affiliations: KU Leuven (BE)
Corresponding author: Proost, Paul
ORCID: Metzemaekers, Mieke
Gouwy, Mieke
Proost, Paul
Venue: Cellular & Molecular Immunology
Publisher: Springer Science and Business Media LLC
Published: 2020-04-01
Volume: 17
Issue: 5
Pages: 433-450
ISSN: 1672-7681 (ISSN-L)
2042-0226
DOI: 10.1038/s41423-020-0412-0
PMC: PMC7192912
OpenAlex: W3014824156
Cited by: 570
References: 246
Citations by year: 2026: 75 · 2025: 124 · 2024: 115 · 2023: 110 · 2022: 94 · 2021: 43 · 2020: 9
FWCI: 6.87
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Cellular and Molecular Immunology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Lirias (submittedVersion, other-oa)
Funders: Onderzoeksraad, KU Leuven (C16/17/010)
Fonds Wetenschappelijk Onderzoek (G.0808.18N)
EC | Horizon 2020 Framework Programme (779295)
Rega Foundation
M.M. obtained a PhD fellowship supported by the L’Oréal-UNESCO for Women in Science initiative and the FWO-Vlaanderen
Topics: Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords: neutrophils, chemoattractant receptors, G protein-coupled receptors, atypical chemokine receptors, formyl peptides, anaphylatoxins, chemokines, neutrophil trafficking, neutrophil maturation, inflammation resolution, tissue repair, disease biomarkers, therapeutic target
MeSH terms: Animals, Chemotactic Factors, Disease, Health, Humans, Neutrophils, Signal Transduction, Receptors, Formyl Peptide

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Neutrophil chemoattractant receptors in health and disease: double-edged swords

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