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The functional diversity of neutrophils and clustered polarization of immunity

Cellular & Molecular Immunology volume 17, pages 1212–1214 (2020)Cite this article

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Neutrophils, bone marrow-derived innate immune cells, are among the first defensive and inflammatory responses of the host to infection and other danger signals. Increasing evidence indicates that neutrophils are critically involved in shaping adaptive immunity as professional antigen-presenting cells (APCs).1,2,3 However, neutrophils also negatively regulate inflammatory and immune responses or promote tissue repair and wound healing through multiple approaches.3,4,5 With the widely diverse roles of neutrophils in host homeostasis and diseases, it is necessary to identify new subsets of functionally different neutrophils. Interestingly and importantly, Li et al.6 and Sun et al.7 recently identified N(IL-23) and N(IL-33) subsets, respectively. These findings are of importance for us to fully understand the biological diversity of neutrophils and, even more importantly, could reveal the wider functional polarization of neutrophils beyond the traditional N1/N2 bidirectional polarization.

Accumulating evidence has revealed that neutrophils exhibit considerable functional plasticity and diversity and that there may be distinct neutrophil subsets. Tsuda et al. reported that type 1 neutrophils (N1) with the CD49d+CD11b− phenotype predominately produce IL-12 and CCL3, type 2 neutrophils (N2) display the CD49d−CD11b+ phenotype and mainly produce IL-10 and CCL2, and CD49d−CD11b− resting neutrophils (N0) have no significant cytokine and chemokine productions.8 Tumor-associated neutrophils are proposed to display an antitumorigenic N1 phenotype versus a protumorigenic N2 phenotype.9,10,11 N1 neutrophils express high levels of immune-activating cytokines and chemokines, low levels of arginase, and have a strong tumor cell-killing capability in vitro, presenting antitumor activity, whereas N2 neutrophils induced by TGF-β in tumors display a protumor phenotype. In contrast to circulating neutrophils, splenic neutrophils express B-cell-stimulating factors, such as BAFF, APRIL, and IL-21, as well as B-cell-attracting chemokines, such as CXCL12 and CXCL13, to promote immunoglobulin class switching, somatic hypermutation, and antibody production.12 In recent studies reported by Li et al., after stimulation with more than ten cytokines, only IL-23 treatment promoted Th17-like neutrophil polarization (referred to as N(IL-23) cells); these neutrophils selectively produce IL-17A, IL-17F, and IL-22 at the mRNA and protein levels and displays a distinctive gene expression profile compared with those of N0 and LPS-treated neutrophils (referred to as N(LPS) cells). IL-23 induces N(IL-23) polarization via STAT3-dependent RORγt and BATF pathways.6 Importantly, these N(IL-23) cells are detectable in DSS-induced colitis and are involved in the pathogenesis of DSS-induced colitis in an IL-17-dependent manner.6 In contrast, IL-33 induces Th9-like neutrophil polarization (referred to as the N(IL-33) cell subset).7 These N(IL-33) cells express and produce high levels of IL-9 and certain quantities of IL-4, IL-5, and IL-13 by activating c-Jun N-terminal kinase- and NF-κB-dependent pathways.7 Compared with N0, N(LPS), and N(IL-23) cells, these N(IL-33) cells display a unique gene expression profile, as determined by RNA-seq assays7 (unpublished data). Importantly, N(IL-33) neutrophils are found in the lungs of OVA-induced allergic inflammation mice, as detected by flow cytometry. The adoptive transfer of the induced N(IL-33) neutrophils markedly enhances the severity of the lung pathology in these allergic inflammation mice.7 The discovery of functionally different neutrophil subsets, such as N(IL-23) and N(IL-33), in both in vitro and in vivo systems strongly supports the hypothesis that neutrophil functional diversity and differential polarization occurs in various microenvironments. The potential ability of neutrophils to polarize to functionally distinct subpopulations may be dependent on their developmental stage, surrounding cytokines and microenvironment. However, our understanding of the induction factors and intracellular signals and the pathogenesis contribution of these newly identified neutrophil subpopulations is still very limited and needs to be explored in the future. The contribution of the newly identified neutrophil subsets, such as N(IL-23) and N(IL-33), to different diseases and graft rejection, must be determined. We should also investigate whether human neutrophils have the same subpopulations as mice and, if so, what their roles are in inflammatory disease and organ allograft rejection. We believe that with the development of single-cell RNA sequencing technology, an increasing number of neutrophil subpopulations will be uncovered in the coming days. Considering the wide range of roles neutrophils play in host homeostasis and disease, it is essential to comprehensively understand the regulatory roles of different neutrophil subpopulations in physiological and pathological situations and to explore novel therapeutic approaches for selectively targeting these subpopulations to treat neutrophil-related diseases.

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Acknowledgements

The authors wish to thank Dr. Zhanfeng Liang for his critical reading of the paper. This work was supported by grants from the National Key Research and Development Program of China (2017YFA0105002 and 2017YFA0104402 to Y.Z.), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030301), the Chinese Government 13th Five-Year Plan (2017ZX10201101), the National Natural Science Foundation for General and Key Programs (C81530049, U1738111, and C31470860 to Y.Z.), and the China Manned Space Flight Technology Project (TZ-1 to Y.Z.).

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  1. These authors contributed equally: Yanan Xu, Qian Zhang

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Yanan Xu, Qian Zhang & Yong Zhao

  2. University of Chinese Academy of Sciences, Beijing, China

    Yanan Xu, Qian Zhang & Yong Zhao

  3. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

    Yong Zhao

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Correspondence to Yong Zhao.

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Xu, Y., Zhang, Q. & Zhao, Y. The functional diversity of neutrophils and clustered polarization of immunity. Cell Mol Immunol 17, 1212–1214 (2020). https://doi.org/10.1038/s41423-020-0378-y

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