Macrophages Induce the Inflammatory Response in the Pulmonary Arthus Reaction through G alpha sub(i2) Activation That Controls C5aR and Fc Receptor Cooperation

• Published in: The Journal of immunology (1950) 2005-03, Vol.174 (5), p.3041-3050
• Main Authors: Skokowa, Julia, Ali, Syed R, Felda, Olga, Kumar, Varsha, Konrad, Stephanie, Shushakova, Nelli, Schmidt, Reinhold E, Piekorz, Roland P, Nurnberg, Bernd, Spicher, Karsten, Birnbaumer, Lutz, Zwirner, Joerg, Claassens, Jill WC, Verbeek, Josef S, van rooijen, Nico, Koehl, Joerg, Gessner, JEngelbert
• Format: Article
• Language: English
• ISSN: 0022-1767

Complement and Fc gamma 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 Fc gamma R IIB, increased levels of activating Fc gamma R III, and highly induced Fc gamma R-mediated TNF- alpha and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of G sub(i)-type G protein signaling in C5aR-mediated control of the regulatory Fc gamma R system in vitro, and analysis of the various C5aR-, Fc gamma R-, and G sub(i)-deficient mice verifies the importance of G alpha sub(i2)-associated C5aR and the Fc gamma R III-Fc gamma R IIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR-and Fc gamma R III-positive cells into C5aR-and Fc gamma R III-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or Fc gamma R III do not possess any such inducibility of immune complex disease, whereas reconstitution with Fc gamma R IIB-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 G alpha sub(i2)-dependent signal for modulating the two opposing Fc gamma R, Fc gamma R IIB and Fc gamma R III, in the initiation of the inflammatory cascade in the lung Arthus reaction.