2024/12/23 by Roberto Amadio, Giulia Bracchetti, Zahraa Alraies +11 · 1 voice
Immunology and Microbiology · Biochemistry, Genetics and Molecular Biology · #Immune cells in cancer #Nuclear Structure and Function #Phagocytosis and Immune Regulation
paper · pdf · doi:10.1101/2024.12.23.630061
openalex publication_date 2024/12/23 · openalex created_date 2024/12/26 · openalex updated_date 2026/07/15
Abstract Mutations in the immune-specific actin regulator WASp induce a proinflammatory state in myeloid cells, whose underlying causes remain poorly defined. Here, we applied microfabricated tools that mimic tissue mechanical forces to explore the role of WASp in connecting mechano-sensing to the activation of inflammatory responses in macrophages. We show that WASp-deficient macrophages carry alterations in nuclear structure and undergo increased blebbing and nuclear rupture when exposed to mechanical confinement. High-resolution imaging indicates that WASp drives the formation of protective perinuclear actin structures in response to confinement. Functionally, a proinflammatory gene signature linked to nuclear envelope rupture is preferentially active in confined WASp null macrophages, which partially depends on the cGAS-STING pathway of cytosolic DNA sensing. Analysis of transcriptional datasets of human and mouse tissue macrophages confirmed elevated inflammatory activation in WASp null cells. Together, these data uncover that WASp restricts pro-inflammatory activation of macrophages by preserving nuclear integrity in confined environments, providing novel clues to understand inflammatory activation in Wiskott-Aldrich Syndrome.