Gene expression changes during the inflammatory phase after enthesis injury

The repair of injured enthesis remains a challenging clinical issue in sports medicine due to dysregulated inflammation and limited regenerative capability. Nevertheless, the mechanisms through which this dysregulated inflammation deteriorates the regenerative niche of enthesis remain unclear. Here, we found that Nlrp3 inflammasomes were activated in macrophages after enthesis injury and subsequently suppressed the regeneration. Nlrp3 inflammasomes generated a proinflammatory niche through an imbalance between the pro-inflammatory factor IL-1β and anti-inflammatory factors including IL-10 and IL-13. Mechanistically, IL-1β was identified as an inhibitory inflammation signaling in proinflammatory niche, reducing the differentiation and migration of stem cells. Moreover, the P2rx7 receptors were verified as an activation signal for Nlrp3 inflammasome post-injury, and conditional knockout of P2rx7 receptors on myeloid cells promoted enthesis regeneration. Together, these results illustrate that Nlrp3 inflammasome generates a proinflammatory niche to suppress enthesis regeneration, and demonstrate that the P2rx7/Nlrp3 inflammasome axis and IL-1β are promising niche-directed regenerative therapeutic targets for enthesis injury treatment.