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BBB seminar: Cory M. Hogaboam

TAM'ing the inflammatory and remodeling responses in chronic lung disease

Cory M. Hogaboam
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Today’s presentation will address our ongoing research efforts in two inter-related areas of lung disease, namely allergic asthma and idiopathic pulmonary fibrosis (IPF). These diseases are linked by the common pathological feature of fibrotic remodeling and a common disease-driving pathway mediated by Gas6 and TAM receptor activation. With respect to asthma, Aspergillus fumigatus is clinically important fungus in both the initiation and the exacerbation of allergic asthmatic responses. Recognition of Aspergillus allergens through Toll-like receptor (TLR) engagement in dendritic cells and macrophages directs a number of immune events that lead to resolution of the fungal burden and subsequent allergic response but TLR signaling is modulated or negatively regulated during asthma thereby obviating this protective mechanism.

We hypothesized that the negative regulation of TLR activation in the allergic host was mediated by Gas6/TAM receptor activation. We observed that Axl and Mer but not Tyro3 were expressed in macrophages, dendritic cells, and stromal cells in the chronic phase of a fungal model of asthma. Gas6 deficient mice were protected from asthma whereas recombinant Gas6 treatment of asthmatic mice from days 14-28 after Aspergillus spore challenge significantly enhanced airway hyperresponsiveness and airway remodeling. Overall, Gas6/TAM activation in the asthmatic airway subverted innate immunity directed against Aspergillus and promoted Th2-type cytokine pathways required to drive persistent asthma. With respect to IPF, we observed that this clinical disease was characterized by highly aberrant fibroblasts, which progressively abolished lung function in a receptor tyrosine kinase (RTK)-dependent manner. Gas6/Tyro3, Axl, Mertk (TAM) RTK expression and activity was increased in IPF leading us to hypothesize that targeting this RTK pathway inhibited fibroblast activation and the development of pulmonary fibrosis. Gas6 and Axl were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts.

The targeting of this pathway with either specific biologics directed at Gas6 or Axl, or with small-molecule TAM inhibitors demonstrated that the TAM receptor inhibitor BGB324 significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents in the same cells.  Finally, gain or loss of Gas6 expression increased or decreased, respectively, lung fibrotic responses to bleomycin, and treatment with BGB324 inhibited pulmonary fibrosis in a translational IPF model. Thus, Gas6/TAM receptor activity contributes to the activation of both immune and non-immune events that is a major driver of fibrotic lung remodeling, indicating that this pathway is of clinical significance in chronic pulmonary diseases.

Chairperson: James B. Lorens, Department of Biomedicine