Mechanical stress modulates NLRP3 pathway in macrophages

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.105-105.35
• Main Authors: Joshi, Hemant, Almgren-Bell, Alison, Todd, Elizabeth M., Morley, Sharon Celeste
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.105.35

NLRP3 inflammasome activation releases the pro-inflammatory cytokine IL-1b and induces pyroptotic cell death. Dysregulated NLRP3 activation escalates inflammatory diseases such as acute lung injury (ALI), ventilator-induced lung injury (VILI), liver fibrosis, and idiopathic pulmonary fibrosis (IPF). These inflammatory disorders are associated with increased mechanical stress due to changing tissue compliance/stiffness. Resident macrophages sense this mechanical signal via a process known as “mechanotransduction”. However, the underlying mechanism of how mechanotransduction regulates the NLRP3 inflammasome is not fully known. In this study, we are investigating that how NLRP3 pathway is regulated in lung resident macrophages during mechanical stress. To alter substrate compliance, macrophages are cultured on collagen-coated gels with various physiologically relevant stiffness (elastic moduli; measured in kiloPascal (kPa)) prior to NLRP3 activation. We have found that the NLRP3 inflammasome is sensitive to the substrate stiffness. NLRP3 induced IL-1β and pyroptosis-inducing gasdermin-D production were highest on the softest substrate (0.2 kPa) and decreased on a stiffer substrate (64 kPa). However, NLRC4 inflammasome activation was not mechano-responsive, suggesting ASC adaptor mediated cross signaling in mechanotransduction. Further analysis of gene expression using high-throughput RNA-sequencing, revealed altered expression of inflammatory bio-markers on macrophages when substrate stiffness was varied. Further examination of molecular interactions between adhesion-based mechanotransduction and NLRP3 signaling will help in understanding inflammatory diseases such as lung fibrosis. AAI career in Immunology Fellowship, R01-AI104732 and R56 AI104732