Trefoil Factor Family: A Troika for Lung Repair and Regeneration

Abstract

Tissue damage in the upper and lower airways caused by mechanical abrasion, noxious chemicals, or pathogenic organisms must be followed by rapid restorative processes; otherwise, persistent immunopathology and disease may ensue. This review will discuss evidence for the important role served by trefoil factor (TFF) family members in healthy and diseased airways of humans and rodents. Collectively, these peptides serve to both maintain and restore homeostasis through their regulation of the mucous layer and their control of cell motility, cell differentiation, and immune function in the upper and lower airways. We will also discuss important differences in which trefoil member tracks with homeostasis and disease between humans and mice, which poses a challenge for research in this area. Moreover, we discuss new evidence supporting newly identified receptor binding partners in the leucine-rich repeat and immunoglobulin-like domain-containing NoGo (LINGO) family in mediating the biological effects of TFF proteins in mouse models of epithelial repair and infection. Recent advances in our knowledge regarding TFF peptides suggest that they may be reasonable therapeutic targets in the treatment of upper and lower airway diseases of diverse etiologies. Further work understanding their role in airway homeostasis, repair, and inflammation will benefit from these newly uncovered receptor-ligand interactions.

Keywords: CXCR4; CXCR7; LINGO receptors; mucosal epithelium repair; trefoil factor family.

Figure 1.

Localization of TFFs (trefoil factors) in the healthy and diseased airway. TFFs are found in the (A) nasal epithelium, (B) tracheal/bronchial epithelium, and (C) bronchiolar–alveolar transition (club-cell transdifferentiation into goblet cells) and (D) are mostly absent from healthy alveoli but may be located there in the context of cancer. (E) TFF2 is dominant in the mouse lung and is expressed in nasal brushings from pediatric patients with asthma during an attack. CF = cystic fibrosis.

Figure 2.

Contribution of TFFs to mucosal barrier function and repair. (A) TFFs bind the terminal disaccharide of mucin glycoproteins to thicken the mucous layer (box outlined in black), which can constrict the airway. TFF1 (blue) and TFF3 (black) are associated with Muc5AC (epithelial) and Muc5B (epithelial and submucosal). TFF1 has been found around Staph, and Muc5B is required for bacterial clearance in the lung (box outlined in red). (B) Cell migration into a damaged site is required for tissue repair. TFF2 (red) and TFF3 (black) bind with unknown receptors to enhance cell motility synergistically with EGF (epidermal growth factor) and extracellular matrix components. (C) TFF3 and FoxJ1 transcription induce ciliogenesis. In the BADJ, NA injury or allergen exposure induces TFF1 and/or TFF3 in club cells, which can differentiate into epithelial or goblet cells. TFF2 from macrophages induces WNT epithelial expression, which is associated with cell proliferation. (D) TFFs contribute to immune function, including enhancing TNFα-evoked release of IL-6 and IL-8; TFF2-dependent induction of IL-33 in epithelial cells, dendritic cells, and macrophages; type 2 responses; and worm clearance during helminth infection. BADJ = bronchoalveolar duct junctions; EGFR = EGF receptor; NA = naphthalene; Staph = Staphylococcus aureus.

Figure 3.

CXCR (CXC receptor) and LINGO (leucine-rich repeat and immunoglobulin-like domain–containing NoGo) family members as TFF receptors. (A) TFF2 requires CXCR4 for calcium mobilization, ERK1/2 activation, and AKT activation. Antagonism of CXCR4–CXCR7 dimer prevents TFF3-mediated cell migration but does not prevent cell proliferation or MAPK activity. Direct binding has not been demonstrated, indicated by the circled question mark. (B) TFF3 interacts with LINGO2 to competitively reverse LINGO2–EGFR binding, enhancing cell proliferation and protection against helminths. LINGO3 is required for TFF2-mediated repair of nasal epithelial cultures. ERK1/2 = extracellular regulated kinase 1/2; KO = knockout; PLC = primary liver cancer; Src = scrambled; WT = wild-type.