Chemokines and their receptors play multiple and non-overlapping roles in the life cycle of neutrophils. Neutrophils in the human spleen and peripheral blood characterize CXCL12 and CXCL13 expression, along with the production of a variety of other chemokines.
| Chemokines | Mice | person |
| CCL2 | + | + |
| CCL3 | + | + |
| CCL4 | + | + |
| CCL5 | + | – |
| CCL17 | + | + |
| CCL18 | – | + |
| CCL19 | – | + |
| CCL20 | + | + |
| CCL21 | – | + |
| CXCL1 | + | + |
| CXCL2 | + | + |
| CXCL3 | – | + |
| CXCL5 | – | + |
| CXCL6 | – | + |
| CXCL8 | – | + |
| CXCL9 | + | + |
| CXCL10 | + | + |
| CXCL11 | – | + |
| MIP2 | + | – |
Neutrophils express high levels of the CXC chemokine receptors CXCR1 and CXCR2, which bind to seven different chemokines, including CXCL1-3 and 5-8. hCXCR1 is very similar to CXCR2, but the latter only binds CXCL6 and CXCL8.
The role of chemokines on neutrophils
Affects neutrophil production
Front. Immunol.
During the life cycle of neutrophils:
CC-type chemokine binds to CCR1/CCR2 to regulate neutrophil precursor cell proliferation.
The CXCL12-CXCR4 axis is responsible for regulating the release and directed migration of neutrophils from the bone marrow.
Immature neutrophils and senescent neutrophils from immature bone marrow neutrophils, which upregulate the expression of CXCR4 and return to the bone marrow or other tissues along the gradient of CXCL12 for clearance.
CXCR4 can also drive senescent neutrophils into the lungs, spleen, and liver.
APC-functioning neutrophils migrate to LNS via the CCR7-CCL19/21 or CXCL12-CXCR4 axis, and pro-angiogenic neutrophils express high levels of CXCR4, allowing them to migrate to the hypoxic zone.
In a mouse model of allergic inflammation, exogenous allergen challenge induces neutrophil recruitment into the airways via CXCR2 and TLR4-dependent pathways.
Neutrophil differentiation is also affected by atypical chemokine receptors, such as ACKR1 expressed by BM nucleated erythrocytes and ACKR2 expressed by hematopoietic progenitor cells.
Determines the diversity of neutrophil subsets
It has been hypothesized that heterogeneity may be primarily due to the senescence process of circulating neutrophils under homeostatic conditions.
The circadian expression of the transcription factor Bmal1 produced by CXCL2 can work with gut microbes to regulate the circadian oscillations of neutrophils in terms of quantity, morphology, and phenotype. In turn, CXCL2 acts on CXCR2 to induce neutrophil senescence.
Senescent neutrophils in mice are highly expressed with CXCR4. CXCR4 upregulation appears to be involved not only in the retrograde migration that directs neutrophils back to BM, but also in their migration within bone marrow tissue for more efficient engulfment by macrophages.
Regulates neutrophil effector function
Under inflammatory conditions, neutrophils completely alter their chemokine receptor repertoire, down-regulate CXCR2 levels and up-regulate inflammatory CCR1, CCR2, and CCR5.
Chemokines acting on neutrophils can also directly and indirectly regulate angiogenesis. CXCL1 induces neutrophils to produce VEGF-A, while CXCR4+ neutrophils with similar senescence characteristics can be recruited to hypoxic regions where CXCL12 is produced, promoting angiogenesis by releasing MMP9.
The CXCL8-CXCR2 axis has a regulatory effect on ROS production by circulating neutrophils. In fact, it restricts neutrophil rolling ability in an autocrine manner by inducing the shedding of CD62L.
CCR2 mediates high levels of ROS and cytokine migration secreted by neutrophils in the blood of patients with rheumatoid arthritis.
Activated neutrophil subsets expressing CCR7 and CXCR4 can migrate to lymph nodes and act as antigen-presenting cells.
CXCL17 plays an important role in the early pro-inflammatory response by promoting neutrophil recruitment to the site of injury. Deletion of CXCL17 results in dysregulated levels of CXCL1, CXCR2, and IL-6 in mice.
Mediates neutrophil and other immune cell crosstalk
ELR+CXC and inflammatory CC chemokines amplify innate immune cell recruitment. Neutrophils also promote the recruitment of lymphocytes that produce Th1 chemokine CXCL9, 10, and 11 and B cells attract chemokine CXCL13.
Inflammation
CCL2/3/19/20: Recruited neutrophils promote monocyte influx at sites of inflammation primarily by secreting chemokines such as CCL2, CCL3, CCL1, and CCL20.
In a mouse model of experimental autoimmune encephalomyelitis, infiltrating neutrophils secrete CCL2 and CCL20 to recruit Th17 lymphocytes, thereby activating neutrophils to produce cytokines and ROS, and upregulating MHC-II and degranulation. Chemokine-dependent crosstalk between human neutrophils and Th17 cells will accelerate pathogenesis.
In tumors, N2-polarized neutrophils express more CCL2 and CCL5 and have the ability to inhibit effector T cells.
CCL13: Neutrophils can recruit DCs and promote late maturation through the production and direct cellular interaction of lactoferrin, α defensin, and CCL3.
CCL17: In a mouse model of cancer, TAN has the ability to chemically lure Treg cells, primarily through CCL17. At the same time, Treg cells can release CXCL8 (IL-8) to recruit neutrophils.
CCL21: High levels of CCL21 in TME inhibit the immunosuppressive polarization of neutrophils, thereby affecting the efficacy of immunotherapy. CCL21 is upregulated in patients who respond to ICI therapy and thus serves as a predictive biomarker.
CXCL12: responsible for guiding activated CD8+ effector T cells to the site of infection.
参考文献：1. Yang, F., Feng, C., Zhang, X. et al. The Diverse Biological Functions of Neutrophils, Beyond the Defense Against Infections. Inflammation 40, 311–323 (2017). https://doi.org/10.1007/s10753-016-0458-42.Capucetti A, Albano F and Bonecchi R (2020) Multiple Roles for Chemokines in Neutrophil Biology. Front. Immunol. 11:1259. doi: 10.3389/fimmu.2020.012593.Lowry E, Chellappa RC, Penaranda B, Sawant KV, Wakamiya M, Garofalo RP, Rajarathnam K. Cxcl17 is a proinflammatory chemokine and promotes neutrophil trafficking. J Leukoc Biol. 2024 Jan 31:qiae028. doi: 10.1093/jleuko/qiae028. 4.Xu W, Weng J, Xu M, Zhou Q, Liu S, Hu Z, Ren N, Zhou C, Shen Y. Chemokine CCL21 determines immunotherapy response in hepatocellular carcinoma by affecting neutrophil polarization. Cancer Immunol Immunother. 2024 Feb 17; 73(3):56. doi: 10.1007/s00262-024-03650-4.
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