Differences in Wound Healing in Mice with Deficiency of IL-6 versus IL-6 Receptor

IL-6 modulates immune responses and is essential for timely wound healing. As the functions mediated by IL-6 require binding to its specific receptor, IL-6Rα, it was expected that mice lacking IL-6Rα would have the same phenotype as IL-6–deficient mice. However, although IL-6Rα–deficient mice share many of the inflammatory deficits seen in IL-6–deficient mice, they do not display the delay in wound healing. Surprisingly, mice with a combined deficit of IL-6 and IL-6Rα, or IL-6–deficient mice treated with an IL-6Rα–blocking Ab, showed improved wound healing relative to mice with IL-6 deficiency, indicating that the absence of the receptor contributed to the restoration of timely wound healing, rather than promiscuity of IL-6 with an alternate receptor. Wounds in mice lacking IL-6 showed delays in macrophage infiltration, fibrin clearance, and wound contraction that were not seen in mice lacking IL-6Rα alone and were greatly reduced in mice with a combined deficit of IL-6 and IL-6Rα. MAPK activation-loop phosphorylation was elevated in wounds of IL-6Rα–deficient mice, and treatment of wounds in these mice with the MEK inhibitor U0126 resulted in a delay in wound healing suggesting that aberrant ERK activation may contribute to improved healing. These findings underscore a deeper complexity for IL-6Rα function in inflammation than has been recognized previously.