The P2X7R/NLRP3 inflammasome axis suppresses enthesis regeneration through inflammatory and metabolic macrophage-stem cell cross-talk.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40279432.
- Also identified by DOI 10.1126/sciadv.adr4894 and PMC identifier 12024643.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The regeneration of the enthesis remains a formidable challenge in regenerative medicine. However, key regulators underlying unsatisfactory regeneration remain poorly understood. This study reveals that the purinergic receptor P2X7 (P2X7R)/Nod-like receptor family protein 3 (NLRP3) inflammasome axis suppresses enthesis regeneration by amplifying IL-1β-mediated inflammatory cross-talk and suppressing docosatrienoic acid (DTA) metabolic cross-talk. NLRP3 inflammasomes were activated in macrophages following enthesis injury, thereby impairing the histological and functional recovery of the injured enthesis. Single-cell RNA sequencing (scRNA-seq) indicated that <i>Nlrp3</i> knockout attenuated pathological inflammation and ameliorated the detrimental effects of IL-1β signaling cross-talk. Furthermore, NLRP3 inflammasomes suppressed the secretion of anti-inflammatory cytokines (IL-10 and IL-13) and DTA. The NLRP3 inflammasome-mediated secretome reduced differentiation and migration of stem cells. Neutralizing IL-1β or replenishing docosatrienoic acid accelerated enthesis regeneration. Moreover, conditional knockout of <i>P2rx7</i> in myeloid cells attenuated NLRP3 inflammasome activation and facilitated enthesis regeneration. This study demonstrates that the P2X7R/NLRP3 inflammasome axis represents a promising therapeutic target for enthesis repair.
Medical subject headings
- NLR Family, Pyrin Domain-Containing 3 Protein
- Receptors, Purinergic P2X7
- Inflammasomes
- Macrophages
- Regeneration
- Stem Cells