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

Veronica Mendoza-Reinoso,Amy J Koh,Adrianne Kurutz,Laurie K Mccauley,Hernan Roca,Dah Youn Baek,John R Rubin

doi:10.3390/cells9020429

Veronica Mendoza-Reinoso, Amy J Koh + Show 5 more

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https://doi.org/10.3390/cells9020429

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Journal: Cells	Publication Date: Feb 12, 2020
Citations: 14	License type: CC BY 4.0

Affiliation: University of Michigan–Ann Arbor

Abstract

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.

Highlights

IntroductionEfferocytosis of apoptotic cells in the tumor microenvironment, a perpetual process during tumor growth, promotes a pro-inflammatory and immunosuppressive program [4,5,6]
Macrophage efferocytosis of apoptotic cells is essential for human health as it maintains tissue homeostasis by preventing the harmful effects of apoptotic cell accumulation and necrosis [1,2,3].efferocytosis of apoptotic cells in the tumor microenvironment, a perpetual process during tumor growth, promotes a pro-inflammatory and immunosuppressive program [4,5,6]
We found that bone marrow-derived macrophages have a very unique role in the efferocytosis-induced inflammatory gene expression profile, which is likely critical in the acceleration of prostate cancer skeletal metastasis

Summary

Introduction

Efferocytosis of apoptotic cells in the tumor microenvironment, a perpetual process during tumor growth, promotes a pro-inflammatory and immunosuppressive program [4,5,6]. Our group recently identified that bone marrow-derived macrophage engulfment of cancer cells resulted in the production of inflammatory cytokines to promote immunosuppression and tumor growth in bone [7]. It remains unclear how the pro-tumorigenic and immunosuppressive effects of macrophage efferocytosis in bone metastasis are linked to uniqueness of the bone microenvironment. Millions of cells undergo apoptosis in the tumor microenvironment; macrophage-mediated efferocytosis of cancer cells has a crucial role in pro-tumorigenic and

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