NRF2 is a mechanosensitive checkpoint for NLRP3 inflammasome activation.

Physiological extracellular matrix stiffness enables one-signal NLRP3 inflammasome activation in human and mouse phagocytes, and this depends on NRF2 activity.

• Why it matters: The mechanisms behind why NLRP3 needs two signals in vitro but only lipopolysaccharide in vivo are unclear, limiting how well experimental models predict immune behavior.
• What they did: The study tested how ECM stiffness affects NLRP3 activity in human and mouse phagocytes, then used NRF2 requirement and gene regulation to identify Panx1 as an NRF2-regulated promoter of NLRP3 activity.
• The result: NRF2 was necessary for one-signal NLRP3 activation, stiff-matrix macrophages showed higher NRF2 and activity, pulmonary fibrosis alveolar macrophages had reduced NRF2, and NRF2 was required for antitumour immunity from cancer vaccines with NLRP3 agonistic adjuvants.

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