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Revealing the diversity of neutrophil functions and subsets

Cellular & Molecular Immunology volume 18, pages 781–783 (2021)Cite this article

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Several recent studies have shown that diverse neutrophil subsets exhibit distinct phenotypic and functional properties in terms of disease onset and progression.1,2 In a study published in Nature Immunology, Sas et al.3 discovered a new neutrophil subset that promotes neuronal survival and axonal regeneration in the central nervous system (CNS). In an immune-driven CNS axon regeneration model (crush injury of the optic nerve by intraocular injection of zymosan), the authors observed a unique granulocyte subset that had characteristics of immature neutrophils and neuroprotective properties and that drove CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors (Fig. 1). This pro-regenerative neutrophil subset promoted repair in the optic nerve and spinal cord, demonstrating the relevance of this subset across CNS compartments and neuronal populations. These findings related to the phenotypes of beneficial neutrophil subsets in neuroregeneration could ultimately lead to the development of new immunotherapies that reverse CNS damage and restore lost neurological function in a variety of diseases.

Neutrophils have a shorter lifespan than other immune cells, such as macrophages, and are present in a large pool in the bone marrow and spleen; thus, their sole function is thought to be triggering inflammation in the early stage of the immune response. However, research has recently shown that bone marrow-derived leukocytes, especially macrophages, exhibit marked transcriptional and functional plasticity in response to environmental stimuli and that they adapt to stimuli derived from tissues and pathological conditions to establish a diverse subset.5 For example, macrophages in the lungs, intestine, and spleen adopt features that are needed for surfactant clearance, immune tolerance, and iron recycling, respectively.1,6 This suggests that there may also be diverse subset of neutrophils, and in fact, neutrophils are involved in the pathogenesis and repair of many tissues and the induction of macrophage subsets according to pathological findings. For example, in acute liver injury, neutrophil-derived reactive oxygen species induce the establishment of a tissue repair subset of macrophages, and neutrophil-produced factors such as matrix metalloproteinase and fibronectin are involved in tissue repair.1,7 Experiments have shown that depletion of neutrophils delays the repair and functional recovery of the nervous system and lungs.7 Furthermore, transforming growth factor β can induce functionally different subtypes of neutrophils in cancer.8 These results indicate that neutrophils are involved not only in the early stages of the immune response but also in the subsequent exacerbation of and recovery from the disease.1,3 In addition, recovered leukocytes but not activated leukocytes have been shown to improve the prognosis of neurological disorders.9,10 However, the stimuli and transcriptional changes that cause changes in neutrophil subtypes and the subtypes that contribute to tissue repair and neuroprotection remain unclear.

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Fig. 1

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Acknowledgements

We thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanz.com/ac) for editing the English text of a draft of this manuscript. This work was supported by AMED (grant number JP20fk0108129), GSK (grant number A-32), and the Japan Intractable Diseases (Nanbyo) Research Foundation (grant number 2020B02).

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Authors and Affiliations

  1. Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan

    Kiyoharu Fukushima & Hiroshi Kida

  2. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan

    Kiyoharu Fukushima & Hiroshi Kida

  3. Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan

    Kiyoharu Fukushima & Hiroshi Nabeshima

  4. Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Ltd, Shiga, Japan

    Hiroshi Nabeshima

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  1. Kiyoharu Fukushima
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Correspondence to Hiroshi Kida.

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Fukushima, K., Nabeshima, H. & Kida, H. Revealing the diversity of neutrophil functions and subsets. Cell Mol Immunol 18, 781–783 (2021). https://doi.org/10.1038/s41423-021-00638-3

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