Trefoil Factor 2 Promotes Type 2 Immunity and Lung Repair through Intrinsic Roles in Hematopoietic and Nonhematopoietic Cells

Abstract

Trefoil factors (TFFs) are small secreted proteins that regulate tissue integrity and repair at mucosal surfaces, particularly in the gastrointestinal tract. However, their relative contribution(s) to controlling baseline lung function or the extent of infection-induced lung injury are unknown issues. With the use of irradiation bone marrow chimeras, we found that TFF2 produced from both hematopoietic- and nonhematopoietic-derived cells is essential for host protection, proliferation of alveolar type 2 cells, and restoration of pulmonary gas exchange after infection with the hookworm parasite Nippostrongylus brasiliensis. In the absence of TFF2, lung epithelia were unable to proliferate and expressed reduced lung mRNA transcript levels for type 2 response-inducing IL-25 and IL-33 after infectious injury. Strikingly, even in the absence of infection or irradiation, TFF2 deficiency compromised lung structure and function, as characterized by distended alveoli and reduced blood oxygen levels relative to wild-type control mice. Taken together, we show a previously unappreciated role for TFF2, produced by either hematopoietic or nonhematopoietic sources, as a pro-proliferative factor for lung epithelial cells under steady-state and infectious injury conditions.

Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism

“…Tff2 deficiency in all of its potential cellular sources exacerbated lung damage caused by the murine hookworm Nippostrongylus brasiliensis ( N.b. ), and recent data shows that both BM-derived and nonBM-derived TFF2 drives repair 22, 23 . Moreover, recent demonstration that myeloid cells influenced by Type 2 immune responses (i.e.…”

Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

“…TFF2 also antagonizes IL-12 (a cytokine required for inducing IFN-γ production and activating Th1 immune cells) secretion from dendritic cells (DCs) and macrophages ( 83 ). TFF2 also serves as mucosal healers via protecting mucosal damage, promoting cell motility, and alveolar type 2 cell proliferation, and restores pulmonary gas exchange after infection ( 84 , 85 ). TFF2 also induces IL-25 and IL-33 after infection to induce type 2 immunity and repair ( 86 ).…”

LINGO3 interacts with Trefoil factor 2 to enforce mucosal barrier integrity and drive tissue repair during colitis

“…This study provides evidence that the orphan transmembrane protein LINGO3 functions as an essential component for epithelial responsiveness to Trefoil factor 2 (TFF2). This finding is particularly important given the body of evidence indicating that TFF2 regulates epithelial repair, restitution and inflammation within the GI and respiratory tract (7, 14, 15, 25-27). LINGO3 has no known function(s) reported to date, therefore these data suggest we have uncovered a novel regulator of mucosal epithelial cell biology.…”

“…Notably, the Trefoil factor family (TFF1, TFF2, TFF3) peptides drive largely enigmatic pathways of tissue repair and immunoregulation at the mucosal interface (6). Although TFFs are constitutively present within mucus secretions and regulate epithelial biology through restitution, cellular migration, regulation of tight junctions, and inhibition of epithelial cell apoptosis, how these molecules exert these functions is largely unknown (7-10).…”