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i2 Activation That Controls C5aR and Fc Receptor Cooperation1
* Department of Clinical Immunology and
Institute of Medical Microbiology, Medical School Hannover, Hannover, Germany;
Department of Biochemistry and Molecular Biology II, Heinrich Heine University, Dusseldorf, Germany;
Institute of Pharmacology, Berlin Free University, Berlin, Germany;
¶
Laboratory of Signal Transduction, National Institute of Environmental and Health Sciences, National Institutes of Health, Department of Health and Human Sciences, Research Triangle Park, NC 27709;
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Department of Immunology, Georg August University, Gottingen, Germany;
#
Department of Genetics, Leiden University, Leiden, The Netherlands; and
**
Department of Molecular Cell Biology, Vrije University, Amsterdam, The Netherlands
Complement and Fc
R effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. In this study we show that in the lung Arthus reaction, the initial contact between immune complexes and alveolar macrophages (AM) results in plasma complement-independent C5a production that causes decreased levels of inhibitory FcRIIB, increased levels of activating FcRIII, and highly induced FcR-mediated TNF-
and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of Gi-type G protein signaling in C5aR-mediated control of the regulatory FcR system in vitro, and analysis of the various C5aR-, FcR-, and Gi-deficient mice verifies the importance of Gi2-associated C5aR and the FcRIII-FcRIIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR- and FcRIII-positive cells into C5aR- and FcRIII-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or FcRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcRIIB-negative AM results in an enhanced pathology. These data suggest that AM function as a cellular link of C5a production and C5aR activation that uses a Gi2-dependent signal for modulating the two opposing FcR, FcRIIB and FcRIII, in the initiation of the inflammatory cascade in the lung Arthus reaction.
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