Inhibition of inflammasome activation improves the impaired pattern of healing in genetically diabetic mice.

BACKGROUND AND
PURPOSE: Type 2 diabetes impairs the healing process because of an exaggerated and persistent inflammatory response, and an altered expression pattern of angiogenic molecules. We investigated the effects of inflammasome blockade in diabetes-related wound-healings defects, in genetically diabetic mice. EXPERIMENTAL APPROACH: An incisional skin wound model was produced on the back of female diabetic C57BL/KsJ-m +/+ Lept(db) mice (db⁺ /db⁺) and their normal littermates (db⁺ /m⁺). Animals were treated daily with two inflammasome blocking agents, BAY 11-7082 (20  mg·kg⁻¹ i.p.), or Brilliant Blue G (BBG, 45.5 mg·kg⁻¹ i.p.), or vehicle. Mice were killed on 3, 6 and 12 days after skin injury to measure expression of the NOD-like receptor NLRP3, caspase-1, VEGF, the inflammasome adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the chemokine CXCL12. Wound levels of IL-1β and IL-18 were also measured, along with histological assessments of wound tissue and the time to complete wound closure. KEY
RESULTS: During healing, the diabetic mice exhibited increased activation of NLRP3, caspase-1, ASC, IL-1β and IL-18. They also showed a reduced expression of VEGF and CXCL12.Treatment with BAY 11-7082 or BBG, to block activation of the inflammasome, decreased the levels of pro-inflammatory molecules. Histological evaluation indicated that inflammasome blockade improved the impaired healing pattern, at day 12 in diabetic mice, along with a decreased time to complete skin healing. CONCLUSIONS AND IMPLICATIONS: These data strongly suggest that activation of the NLRP3 inflammasome is one of the key contributors to the delayed healing of wounds in diabetic mice.