Neutrophils express/produce a variety of cytokines, including pro-inflammatory/anti-inflammatory cytokines, chemokines, immunomodulatory cytokines, TNF superfamily members, and angiogenic/fibrotic factors.
As technology advances, the more and more defined the cytokines that are identified for the production of neutrophils, the more useful it will be to understand the role of neutrophils in different types of inflammatory processes.
Typically, neutrophils constitute or express and produce cytokines after activation by microenvironmental stimuli. The upstream stimuli include colony-stimulating factor and cytokine receptors, G-protein coupling, Fcγ, complement receptors, and PRR.
In addition to chemokines, pro-inflammatory cytokines are an important part of neutrophils' rapid immune response. Cytokines known to be produced or expressed by human and mouse neutrophils include:
| Mice | person | |
| IL-1α | + | + |
| IL-1β | + | + |
| IL-1Ra | + | + |
| IL-4 | + | + |
| IL-6 | + | + |
| IL-10 | + | + |
| IL-12 | + | + |
| IL-17 | + | + |
| IL-18 | + | + |
| IL-21 | + | + |
| IL-22 | + | + |
| IL-23 | + | + |
| IL-27 | – | + |
| NFI-β | + | + |
| IFN-γ | + | + |
| TGF-β | + | + |
| G-CSF | + | + |
| M-CSF | + | + |
| TNF-α | + | + |
| APRIL | + | + |
| BAFF | + | + |
| MIF | + | – |
| TSLP | – | + |
| SCF | – | + |
IL-1β
IL-1β is a classic inflammatory cytokine, such as in systemic inflammation such as obesity, adipose tissue is able to produce high levels of TNF-α, IL-1β, IL-6, and IL-8, leading to the expansion of neutrophils.
However, neutrophils are also able to rely on interactions with adipocytes to express IL-1β.
In the early stages of adipocyte dysfunction, the initial inflammatory response is characterized by neutrophil infiltration into adipose tissue. Chronic low-grade inflammation of adipose tissue further leads to neutrophil activation.
Neutrophils in obese individuals exhibit an activated phenotype, manifested by increased plasma myeloperoxidase and neutrophil elastase concentrations and increased CD66b expression. Activated neutrophils increase IL-1β expression by stimulating the NF-κB signaling pathway.
Cells
In addition, free fatty acids from fat cell lipolysis can also attract neutrophils and stimulate them to produce more IL-1β, which activates other fat cells and immune cells.
In arthritis models, immune complex-activated neutrophils undergo changes in gene expression and produce IL-1β, which stimulates resident synovial histiocytes (e.g., fibroblast-like synovial cells) to further produce neutrophil-attracting chemokines, resulting in neutrophil functional expansion.
IL-6
Neutrophils are able to express or produce IL-6 for its subsequent function of influencing macrophages. For example, in obesity inflammation, IL-6 signaling drives self-renewal and selective activation of adipose tissue macrophages.
- On the one hand, the IL-6/IL-4Rα signaling pathway can neutralize the proliferation of macrophages and mediate the anti-inflammatory effect on macrophages through IL-4Rα.
- On the other hand, IL-6 can also mediate M2-like polarization and proliferation of macrophages independently of the IL-6/IL-4Rα axis.
- At the same time, IL-6 can increase the production of IL-10.
In autoimmune diseases, a certain percentage of neutrophils exhibit upregulation of IL-6 expression. For example, in lupus nephritis, neutrophils can SLC7A11 provide IL-6 to promote ferroptosis resistance of B cells, and inhibition of SLC7A11 can significantly enhance ferroptosis of B cells and reduce B cell proliferation.
IL-6 also regulates neutrophils and includes:
- mediates IL-8-dependent migration of bone marrow neutrophils;
- regulates neutrophil trafficking in an acute inflammatory environment;
- Induction of neutrophil degranulation;
- Increases the level of neutrophil activation;
- Enhance neutrophil killing ability;
- and the autoimmune disease mechanism caused by reducing its production of IL-17A, among others.
IL-17 and IFN-γ
Neutrophils affect Th17 cell differentiation and function, but there are no human data on the efficacy of neutrophils to directly produce or express IL-17 and IFN-γ.
In mouse models, neutrophils have been found to produce IL-17A homodimers but not IFN-γ during Listeria pneumophila infection. Neutrophils induce anti-inflammatory and antimicrobial functions of IFN-γ in a paracrine manner through their derived IL-17A. In addition, IL-17 produced by neutrophils also coordinates IFN-γ-mediated programming of M1 proinflammatory macrophages.
In a mouse model of renal ischemia-reperfusion injury, IL-23 and IL-12-activated Gr-1+ neutrophils were observed to be the primary source of IL-17A, but not Th17 cells.
For IFN-γ, the conclusions are less uniform. Some mouse models have also suggested that neutrophils secrete IFNγ in response to the immune inflammation generated by pathogen infection, independent of TLR11, and significantly reduce pathogen load, thereby prolonging mouse survival.
Migrating neutrophils are responsible for the production of IFN-γ in the early stages of pneumonia infection, which in turn regulates bacterial clearance in mice. The production of this IFN-γ is independent of factors such as IL-12, CD44, TLR2, TLR4, TRIF and Nrf2.
IL-26: Fuels systemic inflammation
IL-26 belongs to the IL-10 family and has been shown to play an important role in many autoimmune and infectious inflammatory diseases. IL-26 is widely expressed in a variety of vertebrates, from fish to humans, but not in mice and rats.
Its unique features also include the direct killing of extracellular bacteria through the formation of pores, as well as participation in TLR9-mediated DNA sensing, among others. Several studies have also shown that IL-26 plays an important role in psoriasis.
Th17 cells are generally thought to be the most widespread source of IL-26 in inflammatory autoimmune diseases, but new research has found that neutrophils may be the primary IL-26-secreting cells in the autoinflammatory environment.
IL-26 expression levels in pustular psoriasis are much higher than in the more common psoriasis vulgaris, suggesting that IL-26 plays a special role in autoinflammatory psoriasis. And this IL-26, which affects autoinflammation, is mainly derived from neutrophils.
The researchers believe that IL-26 is structurally present in neutrophils and stored in its primary granules, where it is released along with other primary granules during cellular degranulation.
J Exp Med
Although IL-26 cannot activate neutrophils alone, it can trigger an inverse effect on neutrophils through two binding mechanisms.
- On the one hand, it activates keratinocytes through traditional IL-26 receptors, leading to the release of IL-1α and CXC chemokines and concomitant neutrophil recruitment;
- On the other hand, IL-26 after binding to bacterial DNA can activate neutrophils through TLR9, leading to further activation of recruited neutrophils, releasing IL-1β and CXCL8.
参考文献：1. Ackermann J, et al.(2024) IL-6 signaling drives self-renewal and alternative activation of adipose tissue macrophages. Front. Immunol. 15:1201439. doi: 10.3389/fimmu.2024.12014392.Krisztina Futosi, Attila Mócsai; Neutrophil IL-26 fuels autoinflammation. J Exp Med 6 May 2024; 221 (5): e20240229. doi: https://doi.org/10.1084/jem.202402293.Uribe-Querol, E.; Rosales, C. Neutrophils Actively Contribute to Obesity-Associated Inflammation and Pathological Complications. Cells 2022, 11, 1883. https://doi.org/10.3390/cells111218834.Cai S, Batra S, Langohr I, Iwakura Y, Jeyaseelan S. IFN-γ induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense. Mucosal Immunol. 2016 May; 9(3):718-29. doi: 10.1038/mi.2015.95. Epub 2015 Sep 9.5.Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol. 2014 Oct 21;5:508. doi: 10.3389/fimmu.2014.00508.6.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/s10753-016-0458-47.Wang Z, et al. Neutrophil-Derived IL-6 Potentially Drives Ferroptosis Resistance in B Cells in Lupus Kidney. Mediators Inflamm. 2023 May 27;2023:9810733. doi: 10.1155/2023/9810733.
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