The myeloid mineralocorticoid receptor regulates dermal angiogenesis and inflammation in glucocorticoid‐induced impaired wound healing

Abstract

Background and Purpose Delayed wound healing is among the deleterious consequences of over‐activation of the mineralocorticoid receptor (MR) induced by topical dermocorticoids. The role of dermal inflammation and angiogenesis in the benefits of MR blockade is unknown. Experimental Approach Skin wounds were made on C57Bl6 mice after topical pretreatment with the dermocorticoid clobetasol. The impact of topical MR blockade by canrenoate on inflammation, angiogenesis, and the wound macrophage phenotype was analysed 5 days post‐wounding. Similar experiments were conducted on mice with genetic deletion of the MR in myeloid cells. Key Results Topical inhibition of the MR with canrenoate improved delayed wound healing through the resolution of prolonged inflammation in glucocorticoid‐pretreated mouse skin. This effect was associated with a higher ratio of anti‐inflammatory macrophages versus pro‐inflammatory macrophages in wounds treated by canrenoate. Furthermore, MR blockade led to upregulated expression of pro‐angiogenic factors and improved impaired angiogenesis in wounds of glucocorticoid‐pretreated skin. Finally, deletion of MR expression by myeloid cells reproduced the benefits of topical pharmacological MR blockade. Conclusion and Implications Topical MR antagonism facilitates the switching of macrophages towards an anti‐inflammatory phenotype, which improves prolonged inflammation and induces angiogenesis to accelerate wound healing delayed by glucocorticoid treatment.

Spironolactone Eyedrop Favors Restoration of Corneal Integrity after Wound Healing in the Rat

“…Whether the reduced cell infiltration results from the quicker restoration on the epithelial barrier or whether it is the primary effect of SPL cannot be determined; however, it confirms that SPL is released at an efficient concentration in the cornea as SPL did reduce IBA-1 positive cells in the rat model of laser-induced choroidal neovascularization [21] and in the diabetic retina [8]. Interestingly, in the glucocorticoid-impaired skin wound healing model, topical MR antagonists shorten the duration of inflammation by increasing the ratio of anti-inflammatory macrophages versus pro-inflammatory macrophages in wounds [35]. The role of activated and infiltrating dendritic cells in the healing process is complex and highly controlled since disrupted nerves can induce the activation of cells, which also interact with nerves to provide either protective or neurotoxic effects [36].…”

Drug suspending during wound healing effectively weakens immunosuppression‐related complications by preserving CD8+ T cell function

“…Immune cells are critical regulators of wound healing through the secretion of cytokines, lymphokines and growth factors 18 . Immune suppression induced by glucocorticoids showed delayed wound closure which resulted in impaired healing 3,19 . Patients who routinely take immunosuppressive medications have a significantly higher risk of postoperative wound dehiscence than normal people 5 .…”

“…18 Immune suppression induced by glucocorticoids showed delayed wound closure which resulted in impaired healing. 3,19 Patients who routinely take immunosuppressive medications have a significantly higher risk of postoperative wound dehiscence than normal people. 5 To address this problem, the use of drug suspending during wound healing has been suggested and was therefore explored in this study.…”

The Mineralocorticoid Receptor Plays a Crucial Role in Macrophage Development and Function

“…S5 ( 37 )). In humans, it has been shown that the GC-induced delay in wound reepithelialization can be prevented with the application of an MRA ( 54 ), which was attributed to reduced inflammation at the wound site ( 55 ).…”