Efferocytosis and Its Associated Cytokines: A Light on Non-tumor and Tumor Diseases?

Abstract

Billions of cells undergo turnover and die via apoptosis throughout our lifetime. A prompt clearance of these apoptotic cells and debris by phagocytic cells, a process known as efferocytosis, is important in maintaining tissue homeostasis. Accordingly, impaired efferocytosis due to the defective clearance and disrupted stages can lead to a growing number of inflammation- and immune-related diseases. Although numerous studies have shown the mechanisms of efferocytosis, its role in disorders, such as non-tumor and tumor diseases, remains poorly understood. This review summarizes the processes and signal molecules in efferocytosis, and efferocytosis-related functions in non-tumor (e.g., atherosclerosis, lung diseases) and tumor diseases (e.g., breast cancer, prostate cancer), as well as describes the role of involved cytokines. Of note, there is a dual role of efferocytosis in the abovementioned disorders, and a paradoxical effect among non-tumor and tumor diseases in terms of inflammation resolution, immune response, and disease progression. Briefly, intact efferocytosis and cytokines promote tissue repair, while they contribute to tumor progression via the tumor microenvironment and macrophage politzerization. Additionally, this review provides potential targets associated with TAM (TYRO3, AXL, MERTK) receptors and cytokines, such as tumor necrosis factor α and CXCL5, suggesting potential novel therapeutic ways in treating diseases.

Keywords: atherosclerosis; breast cancer; cytokine; efferocytosis; inflammation; leukemia; lung disease; prostate cancer; target; tumor.

Graphical abstract

Figure 1

The Process and Mechanism of Efferocytosis The process of efferocytosis involves four steps, including the recruitment of phagocytic cells and the recognition, phagocytosis, and digestion of apoptotic cells.

Figure 2

Roles and Effects of Impaired Efferocytosis in the Most Often Studied Non-tumor Diseases (A) In atherosclerosis, the impaired efferocytosis because of exposure to oxLDLs and disturbed processes of recognition, such as MERTK cleavage and CD47 upregulation, leads to the formation of necrotic and plaque development. (B) In lung diseases, the inefficient efferocytosis leads to damaged airway and cell necrosis due to an accumulation of neutrophils and released cytokines. As there are different types of phagocytic cells, results of efferocytosis vary among specific lung diseases. (C) During wound healing, the defective efferocytosis cannot clear ACs promptly, resulting in an enlarged wound.

Figure 3

The Dual Function of Intact and Impaired Efferocytosis in Breast Cancer Efficient efferocytosis is stimulated by the SIAH2-NRF1 axis to trigger M2-like macrophage polarization and cytokine (e.g., IL-10, TGF-β) release to create a tolerogenic TME, leading to increased tumor progression and migration. Alternatively, impairing efferocytosis through inhibiting MERTK or NRF1 can lead to secondary necrosis and result in an unfavorable impact in hosts. However, co-inhibition of efferocytosis and necrosis via the MERTK inhibitor and IDO1 inhibitor can suppress tumor progression.

Figure 4

The Role of Intact and Impaired Efferocytosis in Prostate Cancer MFG-E8-mediated efferocytosis can induce M2 polarization of tumor-associated macrophages through the STAT3/SOCS3 pathway. Additionally, cytokines CXCL5 and IL-6 enhance M2 polarization, leading to tumor growth and bone metastasis of prostate cancer. Impairing efferocytosis by trabectedin administration or CXCL5 deficiency can suppress tumor size and bone metastasis.