Phagocytic Communication During Apoptotic Cell Clearance and Inflammation

Clearance of apoptotic cells is essential for tissue homeostasis, development and inflammation resolution; it is carried out by professional phagocytes, such as macrophages, and non-professional phagocytes, such as epithelial cells. In most tissues, such as the lung and the brain, professional and non-professional phagocytes reside in close proximity, but it is not known how they co-regulate the cell clearance process. This thesis research has revealed that macrophages redirect the phagocytosis of epithelial cells and this in turn has functional consequences. Data are presented showing that macrophages secrete insulin-like growth factor-1 (IGF-1) after encountering apoptotic cells or the Th2 cytokines IL-4 and IL-13. This IGF-1 from macrophages dampens uptake of the apoptotic cells but enhances the uptake of significantly smaller microparticles by non-professional phagocytes. The IGF-1 mediated redirection of phagocytosis is rapid and reversible. Moreover, macrophages themselves appear resistant to this IGF-1 effect, maintaining normal phagocytic capacity. In a model of allergic airway inflammation, disruption of IGF-1 signaling in airway epithelial cells results in exacerbated disease. Further, productive IGF-1 signaling is most important during allergen sensitization in limiting tissue inflammation. In addition to IGF-1, alveolar macrophages also secrete microparticles with anti-inflammatory properties, and these microparticles inhibit the expression of a variety of inflammatory cytokines produced by airway epithelial cells exposed to HDM allergen. Collectively, these results provide new insights on communication between phagocytes within a tissue, and how this communication can influence tissue inflammation to allergens.