Expression Levels of Lamin A or C Are Critical to Nuclear Maturation, Functional Responses, and Gene Expression Profiles in Differentiating Mouse Neutrophils

Abstract

Neutrophils mediate critical innate immune responses by migrating to sites of infection or inflammation, phagocytosing microorganisms, and releasing an arsenal of antimicrobial agents, including reactive oxygen species. These functions are shared by other innate immune cell types, but an interesting feature of neutrophils is their hallmark lobulated nuclei. Although why this bizarre nuclear shape forms is still being elucidated, studies of two intermediate filament proteins that associate with the nuclear envelope, lamin A and C, indicate that expression levels of these proteins govern nuclear maturation. These A-type lamins also modulate nuclear stiffness, the loss of which may be critical to the migration of not only neutrophils but also cancer cells that become prone to metastasis. We investigated whether increased expression of either lamin A or C affects neutrophil nuclear morphologic maturation, but more importantly we tested whether overexpression of either lamin also affects neutrophil functional responses, using two mouse myeloid progenitor models that can be induced toward functionally responsive neutrophil-like cells. Collectively, our results demonstrate that overexpression of either lamin A or C not only disrupts nuclear lobulation but also causes aberrant functional responses critical to innate immunity, including chemotaxis, phagocytosis, and reactive oxygen species production. Moreover, the lamin A-overexpressing cells exhibit decreased expression of a critical NADPH oxidase complex factor, gp91 phox , and transcriptomic profiling demonstrated differential expression of a number of myeloid differentiation and functional pathway components. Taken together, these data demonstrate that A-type lamin expression levels modulate not only nuclear morphologic features but also gene expression changes as neutrophils mature. ImmunoHorizons, 2022, 6: 16-35.

Lamin A K97E leads to NF‐κB‐mediated dysfunction of inflammatory responses in dilated cardiomyopathy

“…To emphasize more over the dual aspects of NF‐κB mediated transcription deregulation in cases of loss of functional lamin A, studies have linked downregulated NF‐κB expression to the observed loss of gp91(phox) expression, which may also have effects on chemokine or cytokine‐mediated signal transduction or associated signaling pathways (Szymczak et al., 2022). So, the altered function of lamin A and ensuing aberrant nuclear organization in DCM may be linked to inflammatory or stress responses triggered by mechanobiology and its impact on the NF‐κB regulatory axis (Figure 8).…”

Roles of the nucleus in leukocyte migration

“…53 Overexpression of either lamin A or lamin C disrupts neutrophil nuclear morphology and impairs chemotaxis and other functions. 54 Lamin A/C level is also affected by the activation state of leukocytes. Expression of lamin A/C is low in lymphoid cell lines.…”

“…83,84 Down-regulation of lamin A/C is necessary because overexpression of either lamin isoform greatly reduces the number of multilobed nuclei. 54 How LBR mediates nuclear lobulation is unknown. LBR contains an N-terminal nucleoplasmic domain that binds to lamin B, histones, DNA and HP1, and a C-terminal 8-transmembrane domain that functions as a sterol reductase (Figure 2).…”

“…For example, HL‐60 cells express lamin A/C but their levels gradually decrease after cells are induced into neutrophils 53 . Overexpression of either lamin A or lamin C disrupts neutrophil nuclear morphology and impairs chemotaxis and other functions 54 . Lamin A/C level is also affected by the activation state of leukocytes.…”

“… 82 Defective LBR mRNA splicing and abnormal LBR protein folding also lead to PHA 83,84 . Down‐regulation of lamin A/C is necessary because overexpression of either lamin isoform greatly reduces the number of multilobed nuclei 54 …”