Elsevier

Current Opinion in Cell Biology

Volume 62, February 2020, Pages 135-143
Current Opinion in Cell Biology

Emerging roles for the nucleus during neutrophil signal relay and NETosis

https://doi.org/10.1016/j.ceb.2019.10.007Get rights and content

Abstract

The nucleus houses and protects genomic DNA, which is surrounded by the nuclear envelope. Owing to its size and stiffness, the nucleus is often a barrier to migration through confined spaces. Neutrophils are terminally differentiated, short-lived cells that migrate through tissues in response to injury and infections. The neutrophil nucleus is soft, multilobular, and exhibits altered levels of key nuclear envelope proteins. These alterations result in a multifunctional organelle that serves as a signaling hub during migration and NETosis, a process by which neutrophils release decondensed chromatin decorated with granular enzymes that entrap pathogens. In this review, we present emerging evidence suggesting that a unique, ambiguous cell-cycle state is critical for NETosis and migration. Finally, we discuss how the mechanisms underlying migration and NETosis are evolutionarily conserved.

Introduction

The nucleus is the hallmark of eukaryotes and serves to protect genomic DNA from harm. Genomic DNA is surrounded by and interacts with a nucleoskeleton composed of the nuclear lamins, which are intermediate filaments comprised of Lamin A/C and Lamin B1 and B2 [1]. The lamins give the nucleus its shape and stiffness and play important roles in gene expression, chromatin organization, as well as DNA replication and repair [1]. Importantly, disruption of the lamin network is an essential step during mitosis, when the nuclear envelope (NE) breaks down to allow chromosome segregation to the two daughter cells. The lamins underlie a double membrane system that is fenestrated with nuclear pores, which allow transport between the nucleoplasm and cytoplasm. Collectively, the lamins and double membrane make up the NE [2]. The prototypical nucleus is oval shaped, is stiff compared to the surrounding cytoplasm, and in many cell types is the barrier to migration through narrow constrictions [3]. Long thought to be a relatively static and passive organelle, recent work has revealed that the nucleus and NE play critical roles in many aspects of cell biology including cell polarization, lipid homeostasis, migration, differentiation, and intercellular signaling [∗3, 4, 5].

Neutrophils are the most prevalent leukocytes in human blood. They play key roles in innate immunity and are the body's first response to injury and infection [6]. During neutrophil maturation in the bone marrow, Lamin A/C is downregulated, Lamin B and the Lamin B receptor (LBR) are upregulated, and the nucleus becomes multilobulated and more malleable [7,8] (Figure 1). This malleability allows neutrophils to effectively and rapidly migrate through complex 3D environments and reach sites of injury and infection [∗9, 10, 11]. In addition, the NE of neutrophils is an important site of eicosanoid synthesis, which are required to relay chemotactic signals as neutrophils migrate towards sites of injury or infection [12,13]. The acquisition of cell polarity is a prerequisite for neutrophils to migrate directionally toward chemical cues, or chemotax, and is characterized by the dramatic redistribution of cytoskeletal components during which F-actin and numerous actin-binding proteins are enriched at the front, and myosin II is assembled on the sides and at the back of the cells [14]. Once neutrophils reach sites of infection, they contain the affected area by phagocytosing pathogens and releasing antimicrobial chemicals from cytoplasmic granules. In addition, neutrophils have been shown to release their genomic DNA decorated with toxic enzymes that ensnare and kill microbes in neutrophil extracellular traps (NETs) — a process referred to as NETosis [15].

In this review, we discuss recent advances in our understanding of how the neutrophil nucleus integrates, propagates, and translates signals in the context of chemotaxis and NETosis. For more information about the other roles of the neutrophil nucleus not covered herein, we refer the reader to a recent excellent review on the topic [16].

Section snippets

The neutrophil nucleus is more than a DNA-containing organelle

Once neutrophils reach sites of infection, they have an arsenal of weapons to neutralize pathogens. In addition to their iconic multilobular nucleus, neutrophils are characterized by the presence of distinct cytoplasmic granules [6]. These granules contain enzymes and chemicals that neutralize and kill pathogens. There are four types of granules: secretory vesicles, gelatinase, specific, and azurophilic, listed in order of release based on stimulus intensity, with azurophilic granules releasing

Mitosis during life and death

Mitosis is a part of the cell cycle where the NE breaks down to allow for proper segregation of sister chromatids to daughter cells [36,37]. This process is driven by cyclin dependent kinases (CDKs), which are not expressed in terminally differentiated cells that have exited the cell cycle, such as neutrophils [38]. During mitosis, phosphorylation of Lamin A/C weakens the nuclear lamina to facilitate NE breakdown. Nuclear lamina phosphorylation and disintegration of nuclear membranes allow the

Not all signal relay lead to NETosis

Neutrophils are not the only cell type to perform signal relay to amplify primary chemoattractants and enhance collective cell migration. The social amoebae, Dictyostelium discoideum, also relies on autocrine and paracrine signaling during chemotaxis. In response to starvation, Dictyostelium cells enter a developmental program that ultimately leads to the formation of a fruiting body, which harbors spores that can withstand harsh environmental conditions until more favorable conditions arise [60

Conclusions and perspective

Since their identification in 2004, NETs have been an area of intense research. However, what exactly constitutes a NET, what are the contributions from genomic and mitochondrial DNA, and under what conditions NETs are produced represent areas of intense research [74]. An open question raised by Boeltz et al. [74] is whether there is a connection between NETosis and neutrophil swarming. Stephen et al. [33] observed NETs in swarming neutrophils after the injection of adjuvant. Owing in part to

Conflict of interest statement

Nothing declared.

Acknowledgements

The authors thank members of the Parent laboratory for critical input, and Subhash Arya, Pierre Coulombe, Ann Miller, and Shuvasree SenGupta, for reading the manuscript and for very helpful input. CAS received a fellowship from the American Heart Association. Research in the Parent laboratory is supported by internal funds from the University of Michigan. We apologize to the many excellent contributions and findings that we were unable to mention because of space constraints.

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