The Neutrophil Nucleus: An Important Influence on Neutrophil Migration and Function

Abstract

Neutrophil nuclear morphology has historically been used in haematology for neutrophil identification and characterisation, but its exact role in neutrophil function has remained enigmatic. During maturation, segmentation of the neutrophil nucleus into its mature, multi-lobulated shape is accompanied by distinct changes in nuclear envelope composition, resulting in a unique nucleus that is believed to be imbued with extraordinary nuclear flexibility. As a rate-limiting factor for cell migration, nuclear morphology and biomechanics are particularly important in the context of neutrophil migration during immune responses. Being an extremely plastic and fast migrating cell type, it is to be expected that neutrophils have an especially deformable nucleus. However, many questions still surround the dynamic capacities of the neutrophil nucleus, and which nuclear and cytoskeletal elements determine these dynamics. The biomechanics of the neutrophil nucleus should also be considered for their influences on the production of neutrophil extracellular traps (NETs), given this process sees the release of chromatin “nets” from nucleoplasm to extracellular space. Although past studies have investigated neutrophil nuclear composition and shape, in a new era of more sophisticated biomechanical and genetic techniques, 3D migration studies, and higher resolution microscopy we now have the ability to further investigate and understand neutrophil nuclear plasticity at an unprecedented level. This review addresses what is currently understood about neutrophil nuclear structure and its role in migration and the release of NETs, whilst highlighting open questions surrounding neutrophil nuclear dynamics.

Transport and programmed release of nanoscale cargo from cells by using NETosis

“…43 The nuclei (blue), on the other side, remained rather at the middle/front of the cell during migration as previously described. 44 Uptake of SWCNTs increased with concentration and incubation time as evidenced by the nIR fluorescent signal inside the cells (Fig. 2b).…”

Analysis of receptor-ligand pairings and distribution of myeloid subpopulations across the animal kingdom reveals neutrophil evolution was facilitated by colony-stimulating factors

“…This requires the neutrophil's physical form to have high deformability and flexibility as it encounters the different diameters of the vasculature. The neutrophil nucleus is functionally adapted to this role because of its multinucleated structure and the distinct protein composition of the nuclear envelope, features that are widely conserved across mammalian species [47]. CSF3 in co-ordination with C/EBP and the ETS factors; Pu.1 and GA-binding protein (GABP) are responsible for the transcriptional control of the essential neutrophil nuclear structural proteins Lamin A, Lamin C and Lamin B receptor (LBR) [48,49].…”

“…CSF3 in co-ordination with C/EBP and the ETS factors; Pu.1 and GA-binding protein (GABP) are responsible for the transcriptional control of the essential neutrophil nuclear structural proteins Lamin A, Lamin C and Lamin B receptor (LBR) [48,49]. In comparison to other cell nuclear protein compositions, neutrophils have a low proportion of Lamin A and Lamin C, which is believed to make the nucleus more flexible for easier transit [47][48][49]. In contrast, the levels of LBR are increased, which is required for nuclear lobulation and subsequent neutrophil maturation [47,48].…”

“…In comparison to other cell nuclear protein compositions, neutrophils have a low proportion of Lamin A and Lamin C, which is believed to make the nucleus more flexible for easier transit [47][48][49]. In contrast, the levels of LBR are increased, which is required for nuclear lobulation and subsequent neutrophil maturation [47,48]. Therefore, CSF3 signalling and C/EBP are intrinsic to the evolution of neutrophil cell motility.…”

Programmed transport and release of nanoscale cargo by immune cells

“…[42] The nuclei, on the other side, stayed rather at the middle/front of the cell during migration as previously described. [43] Uptake of SWCNTs increased with concentration and incubation time as evidenced by the nIR fluorescent signal inside the cells (Fig. 2b).…”