Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice

Abstract

The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of these wounds are sufficient to activate the inflammasome, as wound-conditioned medium activates caspase-1 and induces release of interleukin (IL)-1β and IL-18 in cultured Mp via a reactive oxygen species–mediated pathway. Importantly, inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds, induced a switch from proinflammatory to healing-associated Mp phenotypes, and increased levels of prohealing growth factors. Furthermore, data generated from bone marrow–transfer experiments from NLRP-3 or caspase-1 knockout to db/db mice indicated that blocking inflammasome activity in bone marrow cells is sufficient to improve healing. Our findings indicate that sustained inflammasome activity in wound Mp contributes to impaired early healing responses of diabetic wounds and that the inflammasome may represent a new therapeutic target for improving healing in diabetic individuals.

Drug delivery strategies to control macrophages for tissue repair and regeneration

“…The authors attributed these results to the short half-life of dexamethasone, so that an initial inhibition of inflammation was able to return once its bioactivity diminished around day 4 postimplantation. 37 It is possible that a strategy that allows a brief period of inflammation to occur prior to its inhibition would aid in biomaterial integration, like it aids chronic wound healing, 34,38 but this strategy has not been explored. Other drug delivery strategies that have been shown to inhibit the foreign body response to biomaterials include the delivery of a blocking antibody to interleukin-4 (IL4), a cytokine that mediates macrophage fusion into foreign body giant cells in vitro and in vivo, 39,40 although it is important to note that the role of IL4 in the foreign body response remains controversial.…”

Distinct cytokine and chemokine patterns in chronic diabetic ulcers and acute wounds

“…The presence and regulation of a number of prominent wound regulators such as IL-1β, IL-6, IL-8, IL-18, bFGF, EGF, VEGF and PDGF have also been reported in previous studies, [7][8][9]10] suggesting our experimental approach to be valid. However, we could not identify an increase in TNF-α or TGF-α as previously seen in chronic wounds.…”

The Role of Myeloid Lineage Cells on Skin Healing and Skin Regeneration

“…This is important in the context of deficient healing which is characterized by excessive inflammation, myeloid cells likely play an important role. Macrophages isolated from diabetic human and mouse wounds have sustained NLRP3 inflammasome activity and IL-1β expression [108,109]. Treating diabetic mouse wounds with a topical pharmacological agent that inhibits NLRP3 inflammasome activity rescues deficient healing [109].…”