Transition from inflammation to proliferation: a critical step during wound healing

Abstract

The ability to rapidly restore the integrity of a broken skin barrier is critical and is the ultimate goal of therapies for hard-to-heal-ulcers. Unfortunately effective treatments to enhance healing and reduce scarring are still lacking. A deeper understanding of the physiology of normal repair and of the pathology of delayed healing is a prerequisite for the development of more effective therapeutic interventions. Transition from the inflammatory to the proliferative phase is a key step during healing and accumulating evidence associates a compromised transition with wound healing disorders. Thus, targeting factors that impact this phase transition may offer a rationale for therapeutic development. This review summarizes mechanisms regulating the inflammation-proliferation transition at cellular and molecular levels. We propose that identification of such mechanisms will reveal promising targets for development of more effective therapies.

Keywords: Bioactive lipid mediator; Fibroblast; Macrophage; MicroRNA; Reactive oxygen species; Toll-like receptor; Transcription factor.

Fig. 1

Negative regulators of Toll-like receptor signaling. TLR2, TLR4, TLR5, TLR9 activate myeloid differentiation primary-response protein 88 (MyD88)-dependent pathway. MYD88-adaptor-like protein (Mal) recruits MyD88 to TLR2 and TLR4. TLR3 activates TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway. In association with TRIF-related adaptor molecule (TRAM), TLR4 can also activate TRIF-dependent pathway. Upon stimulation, MyD88 recruits IL-1 receptor-associated kinase (IRAK), which is activated by phosphorylation and then associates with TNF receptor-associated factor 6 (TRAF6), leading to the activation of transforming growth factor β-activated kinase (TAK1). TAK1 further activates the transcription factors NF-κB and AP-1 through MAPK and NF-κB pathways, respectively. TRIF binds to receptor-interacting protein 1 (RIP1) and TRAF6, also leading to the activation of NF-κB and MAPKs. TRIF also activates interferon regulatory factor 3 (IRF3) through TNFR-associated factor 3 (TRAF3). A plethora of inhibitory mechanisms have been identified in TLR signaling: (i) interference of ligand binding, e.g., soluble forms of TLR2 and TLR4 compete with membrane-bond forms of TLRs for ligands binding; (ii) reduction of TLR expression, e.g., TGF-β suppresses the expression and function of TLR4; (iii) degradation of TLRs, e.g., TRIAD3A binds to the cytoplasmic domain of TLR4 and TLR9 and promotes their ubiquitylation and degradation; (iv) inhibition of TLR downstream signaling, e.g., SOCS1, IRAKM, TOLLIP, IRAK2c/d, A20 and DUSP1; (v) change of structures of target genes through chromatin remodeling and histone modification, e.g., H2AK119 ubiquitylation and H3K27 trimethylation inhibit the expression of TLR-signal-targeted genes; (vi) microRNAs can regulate TLR signaling by targeting TLRs, downstream signaling proteins, related regulatory molecules, transcription factors as well as genes induced by TLR signaling. The figure was made with tools from www.proteinlounge.com

Fig. 2

The roles of macrophage in wound healing. In the early phase of wound repair, upon exposure to pro-inflammatory cytokines, interferons (IFNs), PAMPs or DAMPs, infiltrating monocytes and resident macrophages are activated and mainly acquire a pro-inflammatory M1 phenotype. They perform phagocytosis of microbes, scavenge cellular debris and produce pro-inflammatory mediators. Later during healing process, IL4, IL-10, Glucocorticoids, Prostaglandins (PGs) and modulators of glucose and lipid metabolism induce macrophages to transit to a reparative M2 phenotype, which secret anti-inflammatory mediators and growth factors. Macrophages also remove neutrophils in the wounds by phagocytosis, a central element to induce the M1-M2 phenotype switch of macrophages. The figure was made with tools from www.proteinlounge.com