The Dual Roles of Lamin A/C in Macrophage Mechanotransduction.

Abstract

Cellular mechanotransduction is a complex physiological process that integrates alterations in the external environment with cellular behaviours. In recent years, the role of the nucleus in mechanotransduction has gathered increased attention. Our research investigated the involvement of lamin A/C, a component of the nuclear envelope, in the mechanotransduction of macrophages under compressive force. We discovered that hydrostatic compressive force induces heterochromatin formation, decreases SUN1/SUN2 levels, and transiently downregulates lamin A/C. Notably, downregulated lamin A/C increased nuclear permeability to yes-associated protein 1 (YAP1), thereby amplifying certain effects of force, such as inflammation induction and proliferation inhibition. Additionally, lamin A/C deficiency detached the linker of nucleoskeleton and cytoskeleton (LINC) complex from nuclear envelope, consequently reducing force-induced DNA damage and IRF4 expression. In summary, lamin A/C exerted dual effects on macrophage responses to mechanical compression, promoting certain outcomes while inhibiting others. It operated through two distinct mechanisms: enhancing nuclear permeability and impairing intracellular mechanotransmission. The results of this study support the understanding of the mechanisms of intracellular mechanotransduction and may assist in identifying potential therapeutic targets for mechanotransduction-related diseases.