Role of anaphylatoxins and their receptors in alveolar macrophages functions during allergic asthma
Alveolar macrophages (AMs) comprise alveolus-adherent and non-adherent populationsresiding in the airways and the alveolar lumen. Long considered as garbage collectors clearing potentially dangerous-self or non-self-components from the alveolar space, the AMs are now recognized as a key regulators of pulmonary tolerance. They exert immunosuppressive functions at steady state but can have pro-inflammatory properties under allergic conditions.
We reported in several studies that, at steady state, AMs express high levels of C5aR1 and C5aR2 (Karsten J Immunol2015, Karsten J Immunol2017), but that this expression was downregulated upon allergic asthma conditions (Ender PlosOne2017). In line with these observations, we also reported that conditional depletion of C5aR1 in AMs did not affect the establishment of an allergic asthma phenotype (Wiese PlosOne2017). Interestingly, the screening the tdTomato-C3aR reporter mouse revealed that, in contrast to all the other macrophage populations tested, AMs are the only macrophages that staining negative for tdTomato-C3aR (QuellJ Immunol2017). However, preliminary data suggest that C3aR is upregulated in AMs during the course of allergic asthma.
Our main goal is to define the expression pattern of C3aR, C5aR1 and C5aR2 under allergic asthma conditions. Further, we aim to determine the functional role of C3a and C5a in the distinct AMs with regard to asthma development and perpetuation and using cell-specific conditional AT receptor knockout mice. Also, we aim to define the importance of autocrine C3/C5 production for AM function.
- Hoffmann FM, Berger JL, Lingel I, Laumonnier Y, Lewkowich IP, Schmudde I, König P Distribution and interaction of murine pulmonary phagocytes in the naive and allergic lung. 2018 Front. Immunol., doi.org/10.3389/fimmu.2018.01046
- Quell KM, Karsten CM, Kordowski A, Almeida LN, Briukhovetska D, Wiese AV, Sun J, Ender F, Antoniou K, Schröder T, Schmudde I, Berger JL, König P, Vollbrandt T, Laumonnier Y*, Köhl J*. Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse. J Immunol.2017 199:688-706.
- Wiese AV, Ender F, Quell KM, Antoniou K, Vollbrandt T, König P, Köhl J*, Laumonnier Y*.The C5a/C5aR1 axis controls the development of experimental allergic asthma independent of LysM-expressing pulmonary immune cells. PlosOne2017 12(9):e0184956
- Hoffmann F, Ender F, Schmudde I, Lewkowich I,Köhl J, König P, Laumonnier Y. Origin, localization and immunoregulatoy properties of pulmonary phagocytes in allergic asthma. 2016 Front Immunol 7:107.
Figure 1 Alveolar macrophages express C5aR1 and C5aR2 but are C3aR negative in steady state lungs.(A) Flow cytometry data show that AMs at steady state express C5aR1 and C5aR2, but not C3aR. (B) Under allergic conditions, bronchoalveolar (BAL) and tissue AMs downregulate C5aR1 (dashed vs. solid line).
Figure 2 In contrast to other cells, such as dendritic cells, AMs (stained positively in green for CD11c) are negative for the expression of C3aR (in red) in a tdTomato-C3aR reporter mouse.
Picture made in collaboration with the Institute of Anatomy at the University of Lübeck.