Structured models of ontogenic, phenotypic and functional diversity have been instrumental for a renewed understanding of the biology of immune cells, such as macrophages and lymphoid cells. However, there are no established models that can be used to define the diversity of neutrophils, the most abundant myeloid cells. This lack of an established model is largely due to the uniquely short lives of neutrophils, a consequence of their inability to divide once terminally differentiated, which has been perceived as a roadblock to functional diversity. This perception is rapidly evolving as multiple phenotypic and functional variants of neutrophils have been found, both in homeostatic and disease conditions. In this Opinion article, we present an overview of neutrophil heterogeneity and discuss possible mechanisms of diversification, including genomic regulation. We suggest that neutrophil heterogeneity is an important feature of immune pathophysiology, such that co-option of the mechanisms of diversification by cancer or other disorders contributes to disease progression.

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The authors are grateful to members of their laboratories for continued enthusiasm and discussions, which are reflected in many parts of this text, and to J. M. Adrover and I. Kwok for the original artwork. The authors apologize to the many colleagues whose contributions could not be discussed in this manuscript. This article is supported by Singapore Immunology Network (A*STAR) core funding to L.G.N. This paper is also supported in part by SAF2015-65607-R and Fondo Europeo de Desarrollo Regional (FEDER) to A.H. The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Ministerio de Ciencia, Innovacion y Universidades (MCIU) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MCIU award SEV-2015-0505). Research in the R.O. laboratory is supported by grants from the European Research Council (ERC Starting Grant # 759532, X-TAM), the Italian Telethon Foundation (SR-Tiget grant award F04), the Italian Ministry of Health (GR-2016-02362156), the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG, #20247), the Cariplo Foundation (2015–0990) and the European Union (Infect-ERA #126).

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  1. Singapore Immunology Network (SIgN), A*STAR, Biopolis, Singapore, Singapore

    • Lai Guan Ng
  2. Genomics of the Innate Immune System Unit, San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy

    • Renato Ostuni
  3. Vita-Salute San Raffaele University, Milan, Italy

    • Renato Ostuni
  4. Area of Cell and Developmental Biology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

    • Andrés Hidalgo
  5. Institute for Cardiovascular Prevention, Ludwig Maximillians University, Munich, Germany

    • Andrés Hidalgo


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All authors researched, wrote and edited the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Lai Guan Ng or Renato Ostuni.

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