Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game

Abstract

The interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed.

Figure 1

Simplified scheme for M1 and M2 activation of macrophages. M1 macrophages are induced by LPS or IFN-γ secreting high levels of classical proinflammatory cytokines such as TNF-α, IL-1, IL-6, IL-12, or IL-23, chemokines (e.g., Cxcl9, Cxcl10, and Cxcl5) and increasing their concentrations of NO. In addition, they express high levels of MHC I. IL-4/IL-13 stimulation induces M2 macrophages that downregulate IL-12 and IL-23 expression, release Ccl17, Ccl22 and Ccl24 chemokines and proangiogenic factors, and show increased expression of IL-10. Additionally, they are characterized by expression of MR, Fizz-1, and Ym1.

Figure 2

Alternative activation in ARF-deficient macrophages. In WT macrophages, a balance between M1 and M2 phenotype is established, depending on stimuli. Inflammatory stimuli induce NF-κB signaling pathways through the phosphorylation and subsequent ubiquitin-dependent degradation of IκBα by the 26S proteasome. Then, NF-κB translocates to the nucleus inducing target gene expression. ARF present in the nucleus displays physical and functional interaction with E2F1 resulting in destabilization of E2F1 protein and activation of NF-κB. However, ARF-deficient macrophages establish an immunosuppressive and tolerant microenvironment via impairment of M1 signals. When NF-κB translocates to the nucleus, excessive E2F1 inhibits NF-κB by binding to its subunit p65 in competition with the heterodimeric partner p50. Moreover, excessive E2F1 may inhibit transcriptional expression of TLRs. This leads to secretion of M2 chemokines Ccl17 and Ccl22, release of the anti-inflammatory cytokine IL-10, and stimulation of angiogenesis through expression of VEGF and MMP-9.