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Macrophage Reprogramming by Mycolic Acid Promotes a Tolerogenic Response in Experimental Asthma

Department of Molecular Biomedical Research, Molecular Immunology Unit, Flanders Institute for Biotechnology, Ghent University; Department of Respiratory Diseases, Ghent University Hospital, Ghent; Department of Molecular and Cellular Interactions, Unit of Cellular and Molecular Immunology, Flanders Institute for Biotechnology, Vrije Universiteit Brussel, Brussels; Laboratory of Allergology and Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and Department of Biochemistry, University of Pretoria, South Africa

Correspondence and requests for reprints should be addressed to Prof. Dr. J. Grooten, Department for Molecular Biomedical Research (DMBR), VIB–Ghent University, "Fiers-Schell-Van Montagu" Building, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium. E-mail: johan.grooten{at}dmbr.ugent.be

Rationale: Mycolic acid (MA) constitutes a major and distinguishing cell wall biolipid from Mycobacterium tuberculosis. MA interferes with the lipid homeostasis of alveolar macrophages, inducing differentiation into foamy macrophages exhibiting increased proinflammatory function.

Objectives: We verified the interference of this altered macrophage function with inhaled antigen–triggered allergic airway inflammation and underlying Th2 lymphocyte reactivity.

Methods: Using ovalbumin (OVA) as model allergen, C57BL/6 or BALB/C mice were sensitized by OVA-alum immunization. Experimental asthma, triggered subsequently by repetitive nebulized OVA inhalation, was assessed, using as readout parameters eosinophilia, peribronchial inflammation, and Th2 cytokine function.

Measurements and Main Results: A single intratracheal treatment of sensitized mice with MA, inserted into liposomes as carriers, prevented the onset of OVA-triggered allergic airway inflammation and promoted unresponsiveness to a secondary set of allergen exposures. The development of this tolerant condition required an 8-d lapse after MA instillation, coinciding with the appearance of foamy alveolar macrophages. MA-conditioned CD11b⁺F4/80⁺ macrophages, transferred to the airways, mimicked the tolerogenic function of instilled MA; however, without the 8-d lapse requirement. Indicative of a macrophage-mediated tolerogenic antigen-presenting function, major histocompatibility complex (MHC)–mismatched donor macrophages failed to promote tolerance. Furthermore, Treg markers were strongly increased and established tolerance was lost after in situ depletion of CD25⁺ Treg cells. Contrary to the interleukin-10 dependence of tolerogenic dendritic cells, IFN- deficiency but not interleukin-10 deficiency abrogated the tolerogenic capacity of MA-conditioned macrophages.

Conclusions: These results document an innate-driven Mycobacterium tuberculosis MA-triggered immune regulatory mechanism in control of pulmonary allergic responses by converting macrophages into IFN-–dependent tolerogenic antigen-presenting cells.

Key Words: allergic airway inflammation • foamy macrophages • Mycobacterium tuberculosis • mycolic acid • tolerance

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