The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice

Abstract

The incidence of chronic wounds is escalating, and the associated healing process is especially problematic in an aging population with increased morbidity. Targeting increased inflammation in chronic wounds is a promising but challenging therapeutic strategy. Indeed, inflammation and especially macrophages are required for wound healing. As the NLRP3 inflammasome has been implicated with various other inflammatory diseases, in this study, we used MCC950—a selective NLRP3 small molecule inhibitor—on murine models of both acute and chronic wounds. This molecule, while tested for other inflammatory conditions, has never been investigated to reduce topical inflammation driving chronic wounds. We found that there were no significant differences when the treatment was applied either topically or orally in wild-type C57Bl/6 mice and that it even impaired wound healing in obese mice. The treatment was also unable to improve re-epithelialisation or angiogenesis, which are both required for the closure of wounds. We are inclined to believe that MCC950 may inhibit the closure of chronic wounds and that it does not alter wound-associated macrophage polarisation.

Selective Immunosuppression Targeting the NLRP3 Inflammasome Mitigates the Foreign Body Response to Implanted Biomaterials While Preserving Angiogenesis

“…Instead, surprisingly at the transcriptional level MCC950 appeared to have enhanced pro-angiogenic effects upregulating CDH5, PECAM, KDR, and eNOS gene expression. These effects of MCC950 are in contrast to recent findings in wound healing studies that show MCC950 does not impact angiogenesis [13] or in ischemic retinopathy models that show MCC950 inhibits neovascularization. [27] While the role of NLRP3 in endothelial cells is still not clearly understood, our findings suggest a direct link to both function and integrity in an implant fibrosis setting.…”

<p>In vitro expression of NLRP inflammasome-induced active Caspase-1 expression in normal human epidermal keratinocytes (NHEK) by various exogenous threats and subsequent inhibition by naturally derived ingredient blends</p>

“…MCC950 is a known NLRP3 inhibitor and it may be that the assays discussed here are having a greater impact of the NLRP1 inflammasomes as suggested recently by various research groups. 43,58,59 Nigericin is a known activator of inflammasomes in immune response cells such as dendritic cells and Langerhans cells and was recently examined in CRISP-modified keratinocytes as a potential activator of inflammasome response in keratinocytes. 60 However, in the assays presented here, activation of the NHEKs with Nigericin failed to show an anticipated effect.…”

Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950

“…Evidence exists to support the notion that inhibition of NLRP3 at specific phases may prove beneficial in wound healing. However, no significant change was observed with MCC950 treatment in obese mice, in which wound healing takes longer, or in healthy animals (Lee et al, 2018). There was also a note of possible impairment of wound healing in one treatment Pharmacological Inhibition of NLRP3 with MCC950 group (obese animals treated with a topical application of MCC950).…”