TLR4 Senses Proteinase Activity to Mediate Allergic Lung Disease and Macrophage Fungistatic Response. (117.18)

Asthma is characterized by the presence of T-helper type 2 (Th2) cells in the lung. Our lab has shown that active fungal proteinases are requisite for robust Th2 cell generation and allergic airway inflammation that protects against fungal invasion during airway infection. Macrophages (MΦs) interact with inhaled pathogens and control airway infections via toll like receptors (TLRs) which may play a role in host defense against inhaled fungi. We hypothesized that fungal proteinases activate one or more TLRs in MΦs resulting in allergic lung disease and highly efficient fungal killing. Wildtype mice and mice deficient in specific TLRs (TLR4) and their adaptor molecules (MyD88-/- and TRIF-/- mice) were intranasally infected with viable conidia of Aspergillus niger and assessed for the asthma phenotype. Bone marrow cells were also harvested from TLR4-/- and wildtype mice to assess for differentiation of MΦs via RNA expression of canonical markers and cultured with the viable conidia to determine their effect on fungal growth.TLR4-/- mice failed to develop asthma-like disease while MyD88-/- and TRIF-/- mice had normal or exaggerated responses. Fungal proteinase induced differentiation of naive MΦs that profoundly inhibited fungal growth in vitro in a TLR4 dependent manner. Our findings therefore suggest a “Biased Agonism” model of TLR4 signaling in which distinct ligands may activate alternative signaling pathways that give rise to entirely different immune responses.