Toll-Interacting Protein in Pulmonary Diseases. Abiding by the Goldilocks Principle

Abstract

TOLLIP (Toll-interacting protein) is an intracellular adaptor protein with diverse actions throughout the body. In a context- and cell type-specific manner, TOLLIP can function as an inhibitor of inflammation and endoplasmic-reticulum stress, an activator of autophagy, or a critical regulator of intracellular vacuole trafficking. The distinct functions of this protein have been linked to innate immune responses and lung epithelial-cell apoptosis. TOLLIP genetic variants have been associated with a variety of chronic lung diseases, including idiopathic pulmonary fibrosis, asthma, and primary graft dysfunction after lung transplantation, and with infections, such as tuberculosis, Legionella pneumonia, and respiratory viruses. TOLLIP exists in a delicate homeostatic balance, with both positive and negative effects on the trajectory of pulmonary diseases. This translational review summarizes the genetic and molecular associations that link TOLLIP to the development and progression of noninfectious and infectious pulmonary diseases. We highlight current limitations of in vitro and in vivo models in assessing the role of TOLLIP in these conditions, and we describe future approaches that will enable a more nuanced exploration of the role of TOLLIP in pulmonary conditions. There has been a surge in recent research evaluating the role of this protein in human diseases, but critical mechanistic pathways require further exploration. By understanding its biologic functions in disease-specific contexts, we will be able to determine whether TOLLIP can be therapeutically modulated to treat pulmonary diseases.

Keywords: TOLLIP protein; biomarkers; communicable diseases; genetic research; lung diseases.

Figure 1.

TOLLIP’s (Toll-interacting protein’s) genetic and molecular involvement in idiopathic pulmonary fibrosis (IPF) pathophysiology. TOLLIP reduces mitochondrial ROS, which suppresses the mitochondrial-apoptosis pathway. TOLLIP increases autophagy, which further inhibits apoptosis. TOLLIP levels in IPF vary on the basis of cell type and disease stage (alveolar type II and bronchial epithelial cells separated by dashed horizontal line), but reduced TOLLIP levels may contribute to early IPF development, whereas elevated levels may contribute to late-stage disease progression. The minor allele G for reference SNP 5743890 (rs5743890) is associated with reduced susceptibility and increased mortality from IPF, whereas rs111521887 and rs5743894 have the opposite effect on IPF susceptibility. Solid black arrows indicate positive effects, red lines with perpendicular bars indicate negative effects, and outlined arrows indicate up or down regulation. AT1 = alveolar type 1; AT2 = alveolar type 2; ECM = extracellular membrane; HBE = human bronchial epithelial; MMP7 = matrix metalloproteinase 7; ROS = reactive oxygen species; TGF-β = transforming growth factor-β.

Figure 2.

TOLLIP’s genetic and molecular involvement in asthma pathophysiology. The minor allele G of rs5743899 is associated with reduced TOLLIP expression and subsequently increased airway obstruction. Tollip-KO mice stimulated with IL-13 experience increased IL-33 signaling in alveolar macrophages isolated from Tollip-KO mice (indicated by solid black arrow), which leads to recruitment of inflammatory cells (neutrophils, eosinophils, and lymphocytes), which may exacerbate the asthma phenotype (depicted by a narrowed airway). Mice sensitized to HDMs and exposed to Streptococcus pneumoniae have elevated levels of Tollip in their lungs, which impedes neutrophil recruitment, thereby potentially contributing to asthma exacerbations. Solid black arrows indicate positive effects, red lines with perpendicular bars indicate negative effects, and outlined arrows indicate up or down regulation. Cytokine receptors are depicted by colored lines with nodes. C2 = conserved 2; CUE = coupling of ubiquitin to endoplasmic reticulum degradation; HDM = house dust mite; IL1RAcP = interleukin 1 receptor accessory protein; IL13-Rα1 = interleukin 13 receptor subunit alpha 1; IL4-Rα = interleukin 4 receptor subunit alpha; KO = knockout; ST2L = ST2 receptor; TBD = Myb (TOM)-binding domain.

Figure 3.

TOLLIP’s genetic and molecular involvement in tuberculosis (TB) pathophysiology. The minor allele G of rs5743899 is associated with reduced TOLLIP levels and increased risk of active TB, whereas rs3750920 T allele is associated with increased TOLLIP and reduced risk of active TB. In response to LPS or MTb, monocytes respond with increased IL-6 production and release. TOLLIP inhibits TLR-2/4 signaling, thereby reducing IL-6 inflammatory cascade. Solid black arrows indicate positive effects, red lines with perpendicular bars indicate negative effects, and outlined arrows indicate up or down regulation. C2 = conserved 2; MTb = Mycobacterium tuberculosis; P = phosphate; TLR-2/4 = Toll-like receptors 2 and 4.

Figure 4.

TOLLIP’s genetic and molecular involvement in respiratory virus pathophysiology. The minor allele G of rs5743899 is associated with reduced TOLLIP expression and subsequently increased nasal rhinovirus concentration. In KO TBE cells (indicated by a red X) exposed to rhinovirus and the allergic cytokines IL-13 and IL-33, TOLLIP is unable to inhibit IRAK-1 (IL-1 receptor–associated kinase-1), and its absence also results in reduced IL1-RL1 (IL-1 receptor–like 1) expression, both of which result in increased IL-8, which triggers excessive neutrophilic inflammation. Solid black arrows indicate positive effects, red lines with perpendicular bars indicate negative effects, and outlined arrows indicate up or down regulation. TBE = tracheobronchial epithelial.