Background and PurposeIL‐33 signals through ST2 receptors and induces adaptive and innate inflammation. IL‐33/ST2 is involved in adaptive inflammation‐induced pain. Here, we have investigated the contribution of IL‐33/ST2‐triggered mechanisms to carrageenin‐induced innate inflammation.Experimental ApproachCarrageenin‐ and IL–33‐induced inflammatory responses were assessed in BALB/c‐ (WT) and ST2‐deficient (−/−) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF‐α (infliximab), CXCL1 (antibody to CXCL1), IL‐1 (IL‐1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin).Key ResultsCarrageenin injection increased ST2 and IL‐33 mRNA expression and IL‐33 production in paw skin samples. Carrageenin‐induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2−/− compared with WT mice, effects mimicked by IL‐33 injection in the paw. Furthermore, IL–33‐induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL–33‐induced hyperalgesia in naïve mice was reduced by treatments targeting TNF, CXCL1, IL‐1, endothelin receptors and COX while carrageenin‐induced ST2‐dependent TNF‐α, CXCL1, IL‐1β, IL‐10 and PGE2 production and preproET‐1 mRNA expression. Combining IL‐33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2‐dependent manner.Conclusions and ImplicationsIL‐33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin‐induced inflammation. These data reinforces the importance of IL‐33/ST2 signalling as a target in innate inflammation and inflammatory pain.