Shear-stress initiates signal two of NLRP3 inflammasome activation in LPS-primed macrophages through piezo1
Open accessAbstract
The innate immune system is tightly regulated by a complex network of chemical signals triggered by pathogens, cellular damage, and environmental stimuli. While it is well-established that changes in the extracellular environment can significantly influence the immune response to pathogens and damage-associated molecules, there remains a limited understanding of how changes in environmental stimuli specifically impact the activation of the NLRP3 inflammasome, a key component of innate immunity. Here, we demonstrated how shear stress can act as Signal 2 in the NLRP3 inflammasome activation pathway by treating LPS-primed immortalized bone marrow-derived macrophages (iBMDMs) with several physiologically relevant magnitudes of shear stress to induce inflammasome activation. We demonstrated that magnitudes of shear stress within 1.0 to 50 dyn/cm 2 were able to induce ASC speck formation, while 50 dyn/cm 2 was sufficient to induce significant calcium signaling, gasdermin-D cleavage, caspase-1 activity, and IL-1β secretion, all hallmarks of inflammasome activation. Utilizing NLRP3 and caspase-1 knockout iBMDMs, we demonstrated that the NLRP3 inflammasome was primarily activated as a result of shear stress exposure. Quantitative polymerase chain reaction (qPCR), ELISA, and a small molecule inhibitor study aided us in demonstrating that expression of Piezo1, NLRP3, gasdermin-D, IL-1β, and CCL2 secretion were all upregulated in iBMDMs treated with shear stress. This study provides a foundation for further understanding the interconnected pathogenesis of chronic inflammatory diseases and the ability of shear stress to play a role in their progression.
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Stiffness-driven M1 polarization is facilitated by the Piezo1-YAP axis, while sustained mechanical stimulation promotes a shift toward an M2 phenotype via persistent RhoA/ROCK and STAT6 signaling.
“Stiffnessdriven M1 polarization is facilitated by the Piezo1-YAP axis, while YAP/TAZ inhibition attenuates this inflammatory response (81).”
From The mechanotransduction-immune axis in organ fibrosis: dual regulatory mechanisms and translational therapeutic perspectives (2025) · cites this paper as [82]
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Cellular mechanoactivation of antigen-presenting cells and T cells for cancer immunotherapy
Ghazanfari, D., Ren, L., Cantú, M. S., & King, M. R. (2025) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2025.100619 · Cited by 3 · see citing works
- Authors
- Fish, A., Forster, J., Malik, V., & Kulkarni, A.
- Affiliations
- University of Massachusetts Amherst (US)
- Corresponding author
- Kulkarni, Ashish
- Venue
- ACS Applied Materials & Interfaces
- Publisher
- American Chemical Society (ACS)
- Published
- 2025-01-21
- Volume
- 17
- Issue
- 5
- Pages
- 7363-7376
- ISSN
- 1944-8244 (ISSN-L)
- 1944-8252
- PMC
- PMC12977096
- OpenAlex
- W4406665918
- Cited by
- 20
- References
- 67
- Citations by year
- 2026: 15 · 2025: 5
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Applied Materials & Interfaces (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R35GM147019, T32 GM135096)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- NLRP3 inflammasome, shear stress, Piezo1, ASC speck formation, gasdermin D, caspase-1, IL-1β secretion, calcium signaling, MCP-1, innate immunity, chronic inflammation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Ion Channels, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Stress, Mechanical, Signal Transduction, Caspase 1, Mice, Interleukin-1beta, Inflammasomes
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