Unique Pro-Inflammatory Response of Macrophages during Apoptotic Cancer Cell Clearance

• Published in: Cells (Basel, Switzerland) Switzerland), 2020-02, Vol.9 (2), p.429
• Main Authors: Mendoza-Reinoso, Veronica, Baek, Dah Youn, Kurutz, Adrianne, Rubin, John R, Koh, Amy J, McCauley, Laurie K, Roca, Hernan
• Format: Article
• Language: English
• Subjects: Animals; bone marrow macrophages; bone metastasis; Cell Line, Tumor; Chemokines - metabolism; Coculture Techniques; Communication; Cytokines - metabolism; efferocytosis; Interferon-gamma - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; peritoneal macrophages; Phagocytosis; prostate cancer; tumor associated macrophages
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9020429

The clearance of apoptotic cells by macrophages (efferocytosis) is crucial to maintain normal tissue homeostasis; however, efferocytosis of cancer cells frequently results in inflammation and immunosuppression. Recently, we demonstrated that efferocytosis of apoptotic prostate cancer cells by bone marrow-derived macrophages induced a pro-inflammatory response that accelerated metastatic tumor growth in bone. To evaluate the microenvironmental impact of macrophages and their efferocytic function, we compared peritoneal macrophages (P-MΦ) versus bone marrow-derived macrophages (BM-MΦs) using an efferocytosis in vitro model. The capability to engulf apoptotic prostate cells was similar in BM-MΦs and P-MΦs. Ex vivo analysis of BM-MΦs showed an M2-like phenotype compared with a predominantly M1-like phenotype in P-MΦs. A distinct gene and protein expression profile of pro-inflammatory cytokines was found in BM-MΦs as compared with P-MΦs engulfing apoptotic prostate cancer cells. Importantly, the reprogramming of BM-MΦs toward an M1-like phenotype mitigated their inflammatory cytokine expression profile. In conclusion, BM-MΦs and P-MΦs are both capable of efferocytosing apoptotic prostate cancer cells; however, BM-MΦs exert increased inflammatory cytokine expression that is dependent upon the M2 polarization stage of macrophages. These findings suggest that bone marrow macrophage efferocytosis of apoptotic cancer cells maintains a unique pro-inflammatory microenvironment that may support a fertile niche for cancer growth. Finally, bone marrow macrophage reprogramming towards M1-type by interferon-γ (IFN-γ) induced a significant reduction in the efferocytosis-mediated pro-inflammatory signature.