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

1
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
2
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(2), 429; https://doi.org/10.3390/cells9020429 (registering DOI)
Received: 15 November 2019 / Revised: 1 February 2020 / Accepted: 10 February 2020 / Published: 12 February 2020
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.
Keywords: bone marrow macrophages; peritoneal macrophages; prostate cancer; bone metastasis; tumor associated macrophages; efferocytosis bone marrow macrophages; peritoneal macrophages; prostate cancer; bone metastasis; tumor associated macrophages; efferocytosis
MDPI and ACS Style

Mendoza-Reinoso, V.; Baek, D.Y.; Kurutz, A.; Rubin, J.R.; Koh, A.J.; McCauley, L.K.; Roca, H. Unique Pro-Inflammatory Response of Macrophages during Apoptotic Cancer Cell Clearance. Cells 2020, 9, 429.

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