IL-17 and IL-22 are pivotal cytokines to delay wound healing of S. aureus and P. aeruginosa infected skin

Abstract

IntroductionAlthough the presence of pathogens in skin wounds is known to delay the wound healing process, the mechanisms underlying this delay remain poorly understood. In the present study, we have investigated the regulatory role of proinflammatory cytokines on the healing kinetics of infected wounds.MethodsWe have developed a mouse model of cutaneous wound healing, with or without wound inoculation with Staphylococcus aureus and Pseudomonas aeruginosa, two major pathogens involved in cutaneous wound bacterial infections.ResultsAseptic excision in C57BL/6 mouse skin induced early expression of IL-1β, TNFα and Oncostatin M (OSM), without detectable expression of IL-22 and IL-17A/F. S. aureus and P. aeruginosa wound inoculation not only increased the expression of IL-1β and OSM, but also induced a strong cutaneous expression of IL-22, IL-17A and IL-17F, along with an increased number of infiltrating IL-17A and/or IL-22-producing γδ T cells. The same cytokine expression pattern was observed in infected human skin wounds. When compared to uninfected wounds, mouse skin infection delayed the wound healing process. Injection of IL-1α, TNFα, OSM, IL-22 and IL-17 together in the wound edges induced delayed wound healing similar to that induced by the bacterial infection. Wound healing experiments in infected Rag2KO mice (deficient in lymphocytes) showed a wound healing kinetic similar to uninfected Rag2KO mice or WT mice. Rag2KO infected-skin lesions expressed lower levels of IL-17 and IL-22 than WT, suggesting that the expression of these cytokines is mainly dependent on γδ T cells in this model. Wound healing was not delayed in infected IL-17R/IL-22KO, comparable to uninfected control mice. Injection of recombinant IL-22 and IL-17 in infected wound edges of Rag2KO mice re-establish the delayed kinetic of wound healing, as in infected WT mice.ConclusionThese results demonstrate the synergistic and specific effects of IL-22 and IL-17 induced by bacterial infection delay the wound healing process, regardless of the presence of bacteria per se. Therefore, these cytokines play an unexpected role in delayed skin wound healing.

Oncostatin M Contributes to Airway Epithelial Cell Dysfunction in Chronic Rhinosinusitis with Nasal Polyps

“…To finish, cytokines diffuse in tissues to act in a paracrine way on their membrane receptors. This diffusion has been studied after skin injection of cytokines and could be facilitated on an epithelium whose permeability is increased [ 24 , 59 ]. Targeting OSM could therefore be a therapy of choice by restoring the epithelial barrier and increasing mucociliary clearance.…”

Investigating Inflammatory Markers in Wound Healing: Understanding Implications and Identifying Artifacts

“…IL-17 not only augments their bactericidal capabilities but also aids their migration to the wound site. 29 However, the prolonged or excessive presence of IL-17 can be detrimental to the wound healing process. Research indicates that IL-17 can disrupt normal healing by promoting sustained inflammation and delaying wound closure.…”

“…Its involvement extends to tissue remodeling processes and the promotion of angiogenesis, the creation of new blood vessels that are essential for delivering oxygen and nutrients to healing tissues. 29,55 The dysregulation of IL-22 signaling is a contributing factor to impaired wound healing and the emergence of chronic wound conditions, including diabetic foot ulcers. Understanding the multifaceted role of IL-22 in wound healing not only provides insights into the complex mechanisms of tissue repair but also highlights potential therapeutic targets for chronic wound management.…”

“…Neutrophils, by engulfing bacteria and releasing antimicrobial factors, are indispensable in the initial stages of wound healing. IL-17 not only augments their bactericidal capabilities but also aids their migration to the wound site …”

“…Additionally, IL-22 drives the production of growth factors and key extracellular matrix components, such as collagen, which are vital for the growth and migration of epithelial cells. Its involvement extends to tissue remodeling processes and the promotion of angiogenesis, the creation of new blood vessels that are essential for delivering oxygen and nutrients to healing tissues. , …”