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The Lung Responds to Zymosan in a Unique Manner Independent of Toll-Like Receptors, Complement, and Dectin-1

¹ Department of Pathology and Laboratory Medicine, ⁵ Department of Physiology, and ⁶ Department of Medicine, University of Calgary, Calgary, Alberta, Canada; ² Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; ³ Departments of Surgery and Pharmacology, East Tennessee State University, Johnson City, Tennessee; ⁴ Department of Cell Biology and Immunology, Vrije Universiteit, Amsterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Paul Kubes, Ph.D., Immunology Research Group, Department of Physiology, University of Calgary, Room 1863, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1 Canada. E-mail: pkubes{at}ucalgary.ca

In vitro studies indicate that the inflammatory response to zymosan, a fungal wall preparation, is dependent on Toll-like receptor (TLR) 2, and that this response is enhanced by the dectin-1 receptor. Complement may also play an important role in this inflammatory response. However, the relevance of these molecules within the in vivo pulmonary environment remains unknown. To examine pulmonary in vivo inflammatory responses of the lung to zymosan, zymosan was administered by intratracheal aerosolization to C57BL/6, TLR2- TLR4-, MyD88-, and complement-deficient mice. Outcomes included bronchoalveolar fluid cell counts. We next examined effects of dectin-1 inhibition on response to zymosan in alveolar macrophages in vitro and in lungs of C57BL/6, TLR2-, and complement-deficient mice. Finally, the effect of alveolar macrophage depletion on in vivo pulmonary responses was assessed. Marked zymosan-induced neutrophil responses were unaltered in TLR2-deficient mice despite a TLR2-dependent response seen with synthetic TLR2 agonists. TLR4, MyD88, and complement activation were not required for the inflammatory response to zymosan. Although dectin-1 receptor inhibition blocked the inflammatory response of alveolar macrophages to zymosan in vitro, in vivo pulmonary leukocyte recruitment was not altered even in the absence of TLR2 or complement. Depletion of alveolar macrophages did not affect the response to zymosan. Neither complement, macrophages, nor TLR2, TLR4, MyD88, and/or dectin-1 receptors were involved in the pulmonary in vivo inflammatory response to zymosan.

Key Words: lung diseases • alveolar macrophage • fungus • neutrophils

CLINICAL RELEVANCE The pulmonary innate immune response to zymosan, a fungal wall extract, was found to be independent of complement, Toll-like receptor 2, and/or dectin-1 (unlike in vitro studies), and emphasizes the need for more studies on the response to fungal infections in the lung.