Synergistic action of apoptotic cells and surfactant protein A in boosting IL-4-dependent alternative activation of alveolar macrophages.

Interleukin 4 (IL-4)-mediated activation of macrophages is required for resolution of inflammation and tissue repair. We have previously reported that lung surfactant protein A (SP-A) is necessary for complete IL-4-dependent activation of alveolar macrophages. It is also reported that IL-4Rα signaling requires concomitant recognition and phagocytosis of apoptotic cells and that there is a connection between SP-A and efferocytosis, since SP-A acts as a bridging molecule in the efferocytic process. The objective of this study is to clarify whether SP-A and apoptotic cells act synergistically in boosting alternative activation of macrophages mediated by IL-4. To this end, we cultured alveolar macrophages with IL-4 in the presence and absence of small amounts of apoptotic pneumocytes and SP-A. Under these conditions, both SP-A and apoptotic cells separately did not have any effect on IL-4-mediated activation of macrophages. However, both factors in combination act synergistically, increasing IL-4-dependent alternative activation of alveolar macrophages. Our results suggest that the activation of the tissue repair program in macrophages may require a complex process of integrated multimolecular signaling that is triggered by dead cells and SP-A.