Innate and Adaptive Immune Responses in Wound Epithelialization

Abstract

Significance: Over the years, it has become clear that, in addition to performing their regular duties in immune defense, the innate and adaptive arms of the immune system are important regulators of the complex series of events that lead to wound healing. Immune cells modulate wound healing by promoting cellular cross-talk; they secrete signaling molecules, including cytokines, chemokines, and growth factors. In line with the major effort in wound healing research to find efficient therapeutic agents for the constantly increasing number of patients with chronic wounds, findings regarding the contributions of innate and adaptive immune responses to the re-epithelialization of damaged skin may bring novel therapeutics. Recent Advances: Increasing evidence suggests that induction of the adaptive immune response requires activation of innate immunity and that there is a dependent relationship between the two systems. Consequently, the bridge between the innate and the acquired immune systems has become an area of emerging exploration. It is clear that a better understanding of the epithelial cells (keratinocytes), immune cells, and mechanisms that contribute to an effective wound healing process is necessary so that new strategies for successful wounds treatment can be devised. Critical Issues: A greater understanding of the biology of skin innate and adaptive immune cells during wound epithelialization may have an impact on development of novel strategies for significant improvements in the quality of tissue repair. Future Directions: Future studies should clarify the importance of particular molecules and mechanisms utilized for development and functions of skin-resident γδT and Langerhans cells, as well as identify therapeutic targets for manipulation of these cells to combat epithelial diseases.

Olivera Stojadinovic, MD

Figure 1.

Schematic representation of the general innate and adaptive immune responses in the epidermis and dermis. Upon infection with a pathogen the cells of the innate immune response offer immediate, but short-lasting help. This leads to DC, γδT cell, and iNKT and NK cells activation, which forms the bridge between the innate and adaptive immunity. The cells of the adaptive immune response provide pathogen-specific, long-lasting protection for a proper wound healing process to take place. NK, natural killer. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

Toll-like receptor (TLR) expression in healthy human epidermis. Different studies report diverse expression of TLRs in healthy human epidermis. TLR2 and TLR7 are reported to be diffusely expressed throughout the epidermis with TLR 2 being more pronounced in suprabasal layers of epidermis.^, TLR3 is barely detected in normal human skin. TLR4 is reported to be diffusely expressed with a predominance beneath granular layer.^, TLR5 is reported to be mostly present in basal epidermal keratinocytes. TLR9 expression is weak in stratum basale and stratum spinosum but it is more expressed in upper, more differentiated keratinocytes.

Figure 3.

Dendritic epidermal T-cell (DETC) morphology changes in response to tissue damage. DETC present in normal epidermis (A) have a dendritic morphology. DETC located around a wound (B) become rounded and this morphology change correlates with initiation of a functional response. Epidermal sheets from a C57BL/6J mouse were stained with PE-anti-γδ TCR (mAb GL-3) and confocal images were acquired with a 40× objective. Reproduced with permission from Havran and Jameson, © 2012 The American Association of Immunologists, Inc.

Figure 4.

γδ T cells in murine skin. γδ T cells recognize damaged keratinocytes as those cells displaying the TCR ligand and ligands for NKG2D (e.g., retinoic acid early-1 (Rae-1), ligands for JAML (CAR), and ligands for CD100 (plexin B2). Such cells can be rapidly eliminated because skin γδT cells expressing perforin and granzyme, exert cytolytic functions against virus- or parasite-infected, transformed or stressed keratinocytes.^, Concurrently, γδ T cells may promote wound healing through the release of FGF7, KGF-1, and IGF-1 stimulating neighboring healthy keratinocytes to proliferate. Further, the local secretion of IFN-γ by γδT cells enhances the antimicrobial, antitumor, and other functional activities of NK and αβ T cells, thus maintaining epidermal integrity. CD100 mediates γδT cell morphology changes both in vitro and in vivo and plays a fundamental role in wound repair. Motile dermal γδT cells constitutively expressed the IL-23 receptor (IL-23R) and transcriptional factor RORγt and produce IL-17^, and may be critically involved in cutaneous inflammatory responses. CAR, coxsackie and adenovirus receptor; JAML, junctional adhesion molecule-like protein; IGF, insulin growth factor; FGF, fibroblast growth factor; KGF, keratinocyte growth factor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound