The Role of Toll-Like Receptors and Myeloid Differentiation Factor 88 in Bjerkandera adusta-Induced Lung Inflammation

Background: Recently, a cluster of patients with an intractable allergic fungal cough who were characterized by sensitization to Bjerkandera adusta was reported. In the present study, the role of Toll-like receptors and myeloid differentiation factor 88 (MyD88) in B. adusta-induced lung inflammation was investigated. Methods: Wild-type (WT), TLR2^-/-,TLR4^-/-, and MyD88^-/- BALB/c mice were intratracheally challenged with B. adusta 4 times at 2-week intervals. Lung pathology, bronchoalveolar lavage fluid (BALF) cytological profiles, and inflammatory mediators in BALF were investigated. Bone marrow-derived macrophages (BMDM) from TLR2^-/-,TLR4^-/-, TLR2/4^-/-, TLR7/9^-/-,MyD88^-/-, and WT C57BL/6J mice were stimulated with B. adusta for 12 h, and inflammatory mediators in the culture medium were measured. Results:B. adusta caused lung inflammation along with Th2 cytokine [interleukin (IL)-5 and IL-13] and eosinophil-related chemokine [eotaxin and monocyte chemotactic protein (MCP-3)] production, an increase in eosinophils in BALF, and eosinophil infiltration in the airways in WT and TLR4^-/- mice. However, Th2 and eosinophil-related responses in TLR2^-/- and MyD88^-/- mice were low or undetectable. The induction of neutrophils and IL-6, IL-12, IL-17A, and MCP-1 in the BALF of MyD88^-/- mice was attenuated compared to that in WT mice. The induction of IL-6, TNF-α, MCP-1, and macrophage inflammatory protein-1α was reduced or undetectable in B. adusta-stimulated BMDM from TLR7/9^-/- and MyD88^-/- mice compared to WT mice. Conclusions: These results suggest that TLR2 and the adapter protein MyD88 may play an important role in the induction of eosinophils by B. adusta. However, TLR7/9-MyD88 might be important in the induction of neutrophils and the relevant inflammatory mediators, especially IL-17A.
Int Arch Allergy Immunol 2015;168:96-106

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