Dysregulation of mechanosensing signaling in monocytes of patients with systemic sclerosis is associated with skin inflammation.

Increased stiffness activates human monocytes via mechanosensing, driving SP1-dependent inflammatory gene expression and heightened inflammatory signatures in skin-infiltrating monocytes from systemic sclerosis patients.

• Why it matters: Systemic sclerosis involves immune dysregulation and progressive skin fibrosis, but how fibrotic tissue mechanics regulate monocyte activation and sustain inflammation is unclear.
• What they did: The study reanalyzed single-cell RNA sequencing to compare skin-infiltrating versus circulating monocytes, then used collagen-coated hydrogels spanning physiological and fibrotic stiffness to measure CD86 and inflammatory transcriptional programs. SP1 was tested using CRISPR-Cas9 disruption and pharmacologic inhibition, while YAP/TAZ-TEAD and PIEZO1 were evaluated by lack of evidence and non-reproducing/non-blocking modulation.
• The result: SP1 disruption or inhibition significantly attenuated stiffness-induced inflammatory gene expression, and SSc monocytes showed exaggerated inflammatory responses to high stiffness with reduced wound healing and antifibrotic programs, supporting SP1-dependent mechanosensing as a control pathway.

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