Innate immune cell-epithelial crosstalk during wound repair

Abstract

Skin and intestinal epithelial barriers play a pivotal role in protecting underlying tissues from harsh external environments. The protective role of these epithelia is, in part, dependent on a remarkable capacity to restore barrier function and tissue homeostasis after injury. In response to damage, epithelial wounds repair by a series of events that integrate epithelial responses with those of resident and infiltrating immune cells including neutrophils and monocytes/macrophages. Compromise of this complex interplay predisposes to development of chronic nonhealing wounds, contributing to morbidity and mortality of many diseases. Improved understanding of crosstalk between epithelial and immune cells during wound repair is necessary for development of better pro-resolving strategies to treat debilitating complications of disorders ranging from inflammatory bowel disease to diabetes. In this Review we focus on epithelial and innate immune cell interactions that mediate wound healing and restoration of tissue homeostasis in the skin and intestine.

Figure 1. Epithelial reparative triggers and events.

Cytokines, growth factors, Wnt ligands, SPMs, and MMPs released in the wound microenvironment in response to injury support epithelial cell proliferation as well as migration. Dynamic remodeling of focal adhesion complexes and actin promotes interactions with the ECM that facilitate the epithelial sheet’s migration. Following initial epithelial cell migration, keratinocytes peripheral to the leading edge proliferate and mature to restore epithelial barrier homeostasis and function.

Figure 2. Proinflammatory stage of wound healing.

Neutrophils are the first responders to epithelial injury. They clear bacteria present at the wound site, limiting infection, and secrete proinflammatory TNF-α, which stimulates fibroblast proliferation and angiogenesis.

Figure 3. Resolution of inflammation and repair.

Regenerating epithelial cells express pro-repair molecules including CCL-2, COX2, LGF1, and IL-11, possibly as a result of their activation by TRMs. Wound-associated macrophages (WAMs) and neutrophils also produce pro-repair signals, including annexin A1, VEGF-A, TGF-β, IL-10, and SPMs, that enhance resolution of inflammation at the wound site. In addition to supporting epithelial repair and migration, these pro-repair signals polarize macrophages to M2-like phenotypes that clear apoptotic neutrophils. In the presence of SPMs, neutrophil-derived microparticles may serve as a negative feedback mechanism to suppress additional neutrophil recruitment. TGF-β also stimulates fibroblast differentiation into myofibroblasts, which produce collagen that provides structural support to the healing epithelium.