Caspase-1 modulates incisional sensitization and inflammation.

Background: Surgical injury induces production and release of inflammatory mediators in the vicinity of the wound. They in turn trigger nociceptive signaling to produce hyperalgesia and pain. Interleukin-1β plays a crucial role in this process. The mechanism regulating production of this cytokine after incision is, however, unknown. Caspase-1 is a key enzyme that cleaves prointerleukin-1β to its active form. We hypothesized that caspase-1 is a crucial regulator of incisional interleukin-1β levels, nociceptive sensitization, and inflammation. Methods: These studies employed a mouse hind paw incisional model. Caspase-1 was blocked using the selective inhibitors Ac-YVAD-CMK and VRTXSD727. Nociceptive sensitization, edema, and hind paw warmth were followed in intact animals whereas caspase-1 activity, cytokine, and prostaglandin E 2 levels were assessed in homogenized skin. Confocal microscopy was used to detect the expression of caspase-1 near the wounds. Results: Analysis of enzyme activity demonstrated that caspase-1 activity was significantly increased in periincisional skin. Pretreatment with Ac-YVAD-CMK significantly reduced mechanical allodynia and thermal hyperalgesia. Repeated administration of this inhibitor produced robust analgesia, especially to mechanical stimulation. Administration of VRTXSD727 provided qualitatively similar results. Caspase-1 inhibition also reduced edema and the normally observed increase in paw warmth around the wound site. Correspondingly, caspase-1 inhibition significantly reduced interleukin-1β as well as macrophage-inflammatory protein 1α, granulocyte colony-stimulating factor, and prostaglandin E 2 levels near the wound. The expression of caspase-1 was primarily observed in keratinocytes in the epidermal layer and in neutrophils deeper in the wounds. Conclusions: The current study demonstrates that the inhibition of caspase-1 reduces postsurgical sensitization and inflammation, likely through a caspase-1/interleukin-1β-dependent mechanism.