A Novel Function of Myc-nick, a Cleavage Product of c-Myc, in Resolution of Inflammation

Abstract

Acute inflammatory response is characterized by sequential events including an immediate recruitment of polymorphonuclear leukocytes (PMNs), a subsequent clearance of leukocytes and an eventual resolution. Eventually, restoration of body homeostasis is accomplished when inflammation is resolved successfully, which is underpinned by adaptive immunity at the post-resolution phase. An impaired resolution causes chronic inflammatory response, leading to persistent tissue damage. In the past many years, researchers have focused on developing drugs such as non-steroidal anti-inflammatory drugs to treat patients with inflammatory diseases by shutting off inflammatory response. However, this is not effective in augmenting cellular adaptive response to acute inflammation through potentiation of innate immunity as they often interrupt the consecutive host-protective process. Recent work has been hence shifted to discovery of drugs that actively facilitate resolution of inflammation, achieving a termination of inflammatory response utilizing intrinsic mechanism and a simultaneous recovery of body homeostasis. To achieve the active resolution, two physiologic processes are employed. These include recruitment of leukocytes (typically neutrophils) that eventually die, mostly via apoptosis, after fighting infectious agents and subsequent clearance of dead cells and debris. Macrophages, especially pro-resolving macrophages, are typical cells that are effective on clearance of apoptotic cells by phagocytic engulfment (efferocytosis). These pro-resolving macrophages carries M2 (alternatively activated) phenotypic characteristics. <br/> Carcinogenesis is closely associated with chronic inflammation. Chronic inflammation can cause activation and accumulation of immunosuppressive cells, which favors initial tumor formation and later survival of tumor cells. In recent years, resolution of cancer-associated inflammation is becoming a new approach for cancer therapy. Pro-resolving treatment not only eliminates excessive inflammatory signal, but mediates a post-resolution reaction that generates adaptive immune response. The influx of adaptive immune cells possibly potentiate therapy as these cells have been demonstrated to be effective in immunotherapy. Therefore, it is of great interest to apply pro-resolving strategies for the treatment of inflammatory disorders. <br/> The transcription factor, c-Myc has been known to play a role in manifestation or maintenance of phenotypic characteristics of alternatively activated macrophages. Contradictory to this notion, I found that peritoneal macrophages from zymosan A-treated mice, in the M2-like state, exhibited a markedly reduced level of c-Myc. This was accompanied by accumulation of Myc-nick, a truncated protein generated by a Calpain-mediated proteolytic cleavage of full-length c-Myc. Further, I noticed that the generation of Myc-nick promoted the M2 polarization of macrophages, enhanced the efferocytic capability of these cells and accelerated resolution of inflammation. Another study showed that c-Myc cleavage was not obviously affected by treatment of pro-resolving lipid mediator, resolvin D1 (RvD1), to HCT 116 cancer cells. This is probably due to a lack of Calpain activation during a pro-resolving treatment. It is notable that RvD1 exerts anti-cancer effect by facilitating c-Myc degradation in HCT 116 cells. My studies indicate that Myc-nick might be an innovative therapeutic target in macrophages but not cancer cells. Since tumor-associated macrophages (TAM) are largely present in tumor microenvironment, the role of Myc-nick in the function of TAM merits further investigation in the context of development of novel anticancer strategies. <br/>