Arginase Signalling as a Key Player in Chronic Wound Pathophysiology and Healing

Abstract

Arginase (ARG) represents an important evolutionarily conserved enzyme that is expressed by multiple cell types in the skin. Arg acts as the mediator of the last step of the urea cycle, thus providing protection against excessive ammonia under homeostatic conditions through the production of L-ornithine and urea. L-ornithine represents the intersection point between the ARG-dependent pathways and the urea cycle, therefore contributing to cell detoxification, proliferation and collagen production. The ARG pathways help balance pro- and anti-inflammatory responses in the context of wound healing. However, local and systemic dysfunctionalities of the ARG pathways have been shown to contribute to the hindrance of the healing process and the occurrence of chronic wounds. This review discusses the functions of ARG in macrophages and fibroblasts while detailing the deleterious implications of a malfunctioning ARG enzyme in chronic skin conditions such as leg ulcers. The review also highlights how ARG links with the microbiota and how this impacts on infected chronic wounds. Lastly, the review depicts chronic wound treatments targeting the ARG pathway, alongside future diagnosis and treatment perspectives.

Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury

“…Notably, the serum kynurenine to tryptophan ratio as a measure of Ido1 activity might be used as a disease biomarker 156 . The role of Ido1 and tryptophan metabolism, together with arginine metabolizing enzymes, has been extensively studied in the context of metabolic reprogramming of immune cells for balancing immunoregulatory and pro-inflammatory phenotypes 157 – 159 , thus being critical to wound healing, neoplasia, autoimmunity and the rejection of transplanted tissues 155 , 160 – 162 . Effects of Ido1 activity include promotion of T cell- mediated tolerance and antimicrobial effects 154 and Ido1 might also act at the site of expression to decrease T-cell proliferation and survival, diminishing colonic inflammation and reducing disease severity 155 .…”

Combined metabolomics and network pharmacology to elucidate the mechanisms of Dracorhodin Perchlorate in treating diabetic foot ulcer rats

“…In the last stage of the urea cycle, arginine protects excess ammonia under homeostatic conditions by producing L-ornithine and urea. L-ornithine is located at the intersection of Arg dependent pathway and urea cycle, contributing to collagen production, cell proliferation and detoxification ( Szondi et al, 2021 ). Collagen is an important component of connective tissue; thus, healing requires collagen formation and deposition ( B. Behm, 2012 ).…”

Current research on fungi in chronic wounds

“…Some enzymes are also important in the wound healing process. Arginase (ARG) is a conserved enzyme that can be expressed by multiple skin cell types ( Figure 1 ) ( Szondi, et al, 2021 ). ARGs can play multiple roles in wound healing, such as balancing pro- and anti-inflammatory responses.…”

“…In delayed healing wounds, there is defective ARG signaling, expression and function. Therefore, manipulating the ARG pathway is critical to enhance the healing process and improve the outcomes of patients ( Szondi, et al, 2021 ). It was reported that increased fungal chitin exposure induced host ARG activity and that Candida albicans blocked nitric oxide production in human macrophages by inducing ARG activity, reducing the ability of macrophages to eradicate the fungus ( Wagener, et al, 2017 ).…”