Role of the macrophage-inducible C-type lectin Mincle in the lung host defense against mycobacterial infections in mice

Introduction: The macrophage-inducible C-type lectin Mincle has been shown to serve as a receptor for the mycobacterial cell wall component trehalose dimycolate (TDM, cord factor) of M. tuberculosis. Mincle is associated with FcRγ, an immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor. Therefore, Mincle expressed on activated macrophages may serve to fine-tune innate immune responses of the lung against mycobacterial infections. The aim of the project is to elucidate the role of Mincle in lung protective immunity against inhaled mycobacterial pathogens.

Methods: Characterization of Mincle expression profiles on lung leukocyte subsets in vitro and in vivo under baseline conditions and in response to M. bovis BCG infection was done by flow cytometry. The lung inflammatory response of wild-type mice and Mincle KO mice to infection with M. bovis BCG was also analyzed. Mycobacterial loads in BALF and lung as well as lung draining lymph nodes and spleen were determined by standard plating techniques.

Results: We found that Mincle is induced on macrophages in vitro after stimulation with M. bovis BCG or cord factor, but not by the mycobacterial PAMPs phosphatidyl-inositol mannoside (PIM) or lipoarabinomannan (LAM). Infection of mice with M. bovis BCG time-dependently increased expression of Mincle on alveolar macrophages. BCG-infected Mincle KO mice demonstrated significantly reduced cytokine levels in their BAL fluids relative to wild-type mice, which was accompanied by substantially reduced alveolar leukocyte recruitment profiles in the mutant mice. At the same time, Mincle KO mice showed a strong accumulation of mycobacteria in their lung draining lymph nodes and increased mycobacterial dissemination into their spleens when compared to BCG-infected wild-type mice.

Discussion: Mincle appears to play an important role in lung protective immunity against mycobacterial pathogens. Lack of pulmonary Mincle expression leads to decreased adaptive immune responses in lung draining lymph nodes and allows mycobacteria to rapidly escape towards extrapulmonary organ systems.