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Neutrophil chemoattractant receptors in health and disease: double-edged swords
Open accessAbstract
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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“In the presence of pathogens, different host cells (such as monocytes and macrophages) secrete inflammatory and neutrophil chemoattractant mediators (such as the leukotriene LTB4 involved in inflammation, the interleukin IL-8, and the chemokine CXCL6, a small cytokine belonging to the CXC chemokine family, also known as granulocyte chemotactic protein 2 GCP-2) which bind to specific receptors on”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [215]
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“C-X-C motif chemokine 8 (CXCL8)/interleukin-8 (IL-8) plays definitory roles in tissue response to injury, being the most important neutrophil-attracting and activating chemokine [91].”
BackgroundGetting Your Neutrophil: Neutrophil Transepithelial Migration in the Lung
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“In the final phase, neutrophils reach the apical surface and enter the alveolar space, where they can bind epithelial adhesion molecules and end-target chemoattractants to facilitate their association with the apical surface and engage the source of inflammation (10, 12).”
BackgroundPrat-Luri, B., Neal, C., Passelli, K., Ganga, E., Amore, J., Firmino-Cruz, L., Petrova, T. V., Müller, A. J., & Tacchini‐Cottier, F. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110777 · Cited by 18
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Activation of proresolving macrophages in dorsal root ganglia attenuates persistent arthritis pain
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“Indeed, we suggest that neurons are a likely source of CXCL 1 in day 7 - KBxN - ST DRG in both WT and cKO and this chemokine is a potent chemoattractant for neutrophils that also respond to LTB 4 produced by macrophages ( 37 ).”
Signal integration in forward and reverse neutrophil migration: Fundamentals and emerging mechanisms
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“This also provides another idea for research: to improve multiple adverse effects in obese patients by modulating NETosis (Metzemaekers et al., 2020).”
BackgroundNeutrophil extracellular traps regulating tumorimmunity in hepatocellular carcinoma
Zhu, W., Fan, C., Dong, S., Li, X., Chen, H., & Zhou, W. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1253964 · Cited by 18
“In addition to histones, NET-associated proteins include cytoplasmic, granule, and cytosolic proteins, as well as neutrophil-derived metabolic enzymes (70, 88).”
BackgroundCXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis
Vermeersch, G., Proost, P., Struyf, S., Gouwy, M., & Devos, T. (2024) · Haematologica · doi:10.3324/haematol.2023.284921 · Cited by 16
Self-citationLeukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy
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Neutrophil extracellular traps impair regeneration
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CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology
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“Data from isolated CAMs in naïve conditions revealed their ability to produce different chemoattractants under physiological conditions, including different interleukins and chemokines [18] involved in neutrophil recruitment [14, 30, 32, 34, 35, 41].”
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Lactoferrin modified by hypohalous acids: Partial loss in activation of human neutrophils
Grigorieva, D. V., Gorudko, I. V., Грудинина, Н. А., Panasenko, O. M., Semak, I. V., Av, S., & Timoshenko, A. V. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.11.165 · Cited by 15
The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome
Miyashiro, D., Souza, B. D. C. E., Torrealba, M. P., Manfrere, K. C. G., Sato, M. N., & Sanches, J. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020936 · Cited by 15
“Neutrophils express CXCR2 and are attracted by the Th17 microenvironment [95,96].”
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“Although there are reports that neutrophils express CCR2 and CCR5 under specific conditions, it is generally considered that these receptors are expressed on macrophages, monocytes, lymphocytes, and dendritic cells, but not neutrophils [1,31].”
BackgroundCao, S. “., Nguyen, K. M., Ma, K., Du, X., Liu, X., Antonova, A. U., Rood, R. P., Gremida, A. K., Chen, C.-H., Gutierrez, A. M., et al. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.07.025 · Cited by 15
Langerhans cells orchestrate apoptosis of DNA‐damaged keratinocytes upon high‐dose UVB skin exposure
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Beyond CCR7: dendritic cell migration in type 2 inflammation
Meloun, A., & León, B. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1558228 · Cited by 17
“LTB4 signals through BLT1 and BLT2 receptors (Figure 2) and acts as a potent chemoattractant for neutrophils (91 – 93).”
Neutrophils preserve energy storage in sympathetically activated adipocytes
Son, S., Xu, C., Fu, H., Wisessaowapak, C., Valentine, J. M., An, G., Jang, J., Dinh, M., Dai, Y. D., Fan, W., et al. (2025) · Nature · doi:10.1038/s41586-025-09839-6 · Cited by 19
“33) were not suppressed by p38 inhibition or LTB4 inhibition in early the phase of sympathetic activation, while neutrophil infiltration was reduced, suggesting that these chemokines alone are insufficient to drive the initial neutrophil infiltration.”
Chen, L., Sun, R., Lei, C., Xu, Z., Song, Y., & Deng, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1178498 · Cited by 14
Yan, T., Wang, R., Yao, J., & Luo, M. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002403 · Cited by 14
van der Lans, S. P. A., Bardoel, B. W., Ruyken, M., de Haas, C. J. C., Baijens, S., Muts, R. M., Scheepmaker, L. M., Aerts, P. C., Wout, M. V. '., Preiner, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52372-9 · Cited by 14
“Complement activation on bacteria results in deposition of the opsonin C3b and the release of the anaphylatoxin C5a, which promote phagocytic uptake and killing by human phagocytes 4 .”
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“IACS-70654 also decreased the RNA expression of genes encoding CCR1 and Ly6G, both of which are critical for neutrophil migration (36, 37) (Supplemental Figure 3, H and I, Supplemental Table 14, Supplemental Table 16, and Supplemental Table 18).”
BackgroundAlveolar macrophage function is impaired following inhalation of berry e-cigarette vapor
Kulle, A., Li, Z., Kwak, A., Mancini, M., Young, D. W., Avizonis, D. Z., Groleau, M., Baglole, C. J., Behr, M. A., King, I. L., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2406294121 · Cited by 14
“C5AR1 is important for complement - mediated pathogen recognition, while FPR1 detects formylated peptides on components of both bacterial and dead cells (46, 47).”
BackgroundDisease-specific suppressive granulocytes participate in glioma progression
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The Role of Neutrophils in the Pathogenesis of Chronic Lymphocytic Leukemia
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“In general, the CXCR2 influences the activation status of neutrophils and can be modulated by environmental factors, including TNFα or nitric oxide [41].”
BackgroundLi, Y., Zeng, H., & Zhong, X. (2025) · Clinical Science · doi:10.1042/cs20257865 · Cited by 14
“The C3 cleavage product C3a, along with C5a, acts as a potent chemoattractant, guiding these cells to migrate to sites of vascular damage [82].”
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“…or chemokines have been considered as well-established chemoattractants through their corresponding receptors, such as interleukin-8 (IL-8/CXCL8)-CXC motif chemokine receptor 1 (CXCR1), leukotriene B4 (LTB4)-LTB4 receptor 1/2 (BLT1/2), complement component 5a (C5a)-C5a receptor 1 (C5AR1)/CD88 [26].”
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“However, neutrophils can act as a double-edged sword because their excessive accumulation and release of those antimicrobial mediators can cause tissue damage and contribute to severe disease development [17,18].”
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Granules of immune cells are the source of organelles in the regenerated nerves of crayfish antennae
Kor, G., Mengal, K., Buřič, M., Kozák, P., & Niksirat, H. (2023) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2023.108787 · Cited by 12
Signaling dynamics distinguish high- and low-priority neutrophil chemoattractant receptors
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“These activities are critical for effective immune responses, but their dysregulation is a major cause of tissue damage and chronic inflammation in autoimmune and inflammatory diseases ( 5 – 7 ).”
C-X-C Motif Chemokine Ligand 1 Promotes Colitis by Modulating the Gut Microbiota
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“CXCL1 is a potent chemoattractant for neutrophils, orchestrating their recruitment to sites of in fl ammation [34].”
BackgroundNeutrophils are involved in early bone formation during midpalatal expansion
Jiang, T., Tang, X., Su, H., Chen, J., Qin, Y., Qin, Y., Ouyang, N., & Tang, G. (2023) · Oral Diseases · doi:10.1111/odi.14849 · Cited by 12
Blocking CXCR1/2 attenuates experimental periodontitis by suppressing neutrophils recruitment
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Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish
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Impaired neutrophil migration underpins host susceptibility to infectious colitis.
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Neutrophils in colorectal cancer: mechanisms, prognostic value, and therapeutic implications
Wang, X., He, S., Gong, X., Lei, S., Zhang, Q., Xiong, J., & Liu, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1538635 · Cited by 15
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“C3a tends to attenuate lipopolysaccharide-induced endotoxemia, primarily activating granulocytes rather than neutrophils, while C5a can recruit neutrophils and monocytes to the site of inflammation and activate these cells in these locations [22,23].”
Background
Metadata
- Authors
- Metzemaekers, M., Gouwy, M., & Proost, P.
- Affiliations
- KU Leuven (BE)
- Corresponding author
- Proost, Paul
- Venue
- Cellular & Molecular Immunology
- Published
- 2020-04-01
- Volume
- 17
- Issue
- 5
- Pages
- 433-450
- ISSN
- 1672-7681 (ISSN-L)
- 2042-0226
- 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
- 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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