What Is the Impact of Depletion of Immunoregulatory Genes on Wound Healing? A Systematic Review of Preclinical Evidence

Abstract

Cytokines and growth factors are known to play an important role in the skin wound closure process; however, in knockout organisms, the levels of these molecules can undergo changes that result in the delay or acceleration of this process. Therefore, we systematically reviewed evidence from preclinical studies about the main immunoregulatory molecules involved in skin repair through the analysis of the main mechanisms involved in the depletion of immunoregulatory genes, and we carried out a critical analysis of the methodological quality of these studies. We searched biomedical databases, and only original studies were analyzed according to the PRISMA guidelines. The included studies were limited to those which used knockout animals and excision or incision wound models without intervention. A total of 27 studies were selected; data for animal models, gene depletion, wound characteristics, and immunoregulatory molecules were evaluated and compared whenever possible. Methodological quality assessments were examined using the ARRIVE and SYRCLE’s bias of risk tool. In our review, the extracellular molecules act more negatively in the wound healing process when silenced and the metabolic pathway most affected involved in these processes was TGF-β/Smad, and emphasis was given to the importance of the participation of macrophages in TGF-β signaling. Besides that, proinflammatory molecules were more evaluated than anti-inflammatory ones, and the main molecules evaluated were, respectively, TGF-β1, followed by VEGF, IL-6, TNF-α, and IL-1β. Overall, most gene depletions delayed wound healing, negatively influenced the concentrations of proinflammatory cytokines, and consequently promoted a decrease of inflammatory cell infiltration, angiogenesis, and collagen deposition, compromising the formation of granulation tissue. The studies presented heterogeneous data and exhibited methodological limitations; therefore, mechanistic and highly controlled studies are required to improve the quality of the evidence.

Anti-Inflammatory, Antioxidant, and Skin Regenerative Potential of Secondary Metabolites from Plants of the Brassicaceae Family: A Systematic Review of In Vitro and In Vivo Preclinical Evidence (Biological Activities Brassicaceae Skin Diseases)

“…Murine excisional wound models were the primary animal model used in the studies included in this systematic review about the effects of Brassicaceae on skin edema and wounds (rats and mice, respectively). This is probably because rats and mice have long been the preference for animal models in research in various areas, due to their anatomical, physiological, and especially genetic similarities with humans [ 34 ]. Another important factor is that the greater the uniformity of the animals concerning experimental, environmental, and genetic variables, the smaller the sample size of animals needed to develop the research [ 35 ].…”

“…In addition, females are more sensitive to acute oral toxicity, as well as dermal toxicity, than males [ 14 ]. The age groups of the animals were similar, which is an important feature for studies evaluating wound healing and even intrinsically in studies of the inflammatory process, since aging rats influence the formation of new vessels, wound closure, re-epithelialization, and the resolution of the inflammatory process [ 34 ], due to the activity of enzymes that break down with aging [ 37 ]. Excisional wounds were predominant, although the number and size of wounds were variable.…”

Biomimetic analyses of interactions between macrophages and palmar fascia myofibroblasts derived from Dupuytren's disease reveal distinct inflammatory cytokine responses

“…Most notably, paracrine interactions with PFMs induced a $10-fold increase in IL6 expression in THP-1 macrophages and a corresponding >10-fold increase in IL-6 protein levels in the shared conditioned media (Figure 4). Interactions between IL-6, TNF and TGFβ-1 have been demonstrated in wound healing and fibrosis development, [47][48][49] so it is feasible that similar interactions contribute to DD pathogenesis.…”

Cytokines and Venous Leg Ulcer Healing—A Systematic Review

“…Most of our knowledge regarding the temporal and spatial variations of cytokines in wound healing derives from acute surgical wounds [ 23 , 24 , 25 ]. This knowledge has been supplemented with wound healing studies in knock-out mice models that have convincingly shown that deficiencies of cytokines severely impair wound healing [ 26 , 27 , 28 , 29 ], which underscores the importance of cytokines in normal wound healing.…”