The role of Src kinase in macrophage-mediated inflammatory responses

Abstract

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

Figure 1

The structure of Src.

Figure 2

Schemata of conformational changes of Src.

Figure 3

The role of Src in immune cells. A combination of antigens, cytokines, adhesion molecules, lipid factors, and their different receptors relevant to immune cell development and inflammatory responses. Regardless of the stimulus and the receptor type, Src plays a critical role in recruiting a number of cell signaling molecules. Initiated and activated by the receptor, Src increases and varies the signal. Depending on the signal received, multiple pathways that influence cell migration, adhesion, phagocytosis, cell cycle, and cell survival are activated.

Figure 4

The Src-mediated signaling pathways in TLRs. In the TLR family signaling pathways, Src generally regulates the early steps of the signaling cascades.

Figure 5

The role of Src under conditions of oxidative stress. Src has been shown to control NADPH oxidase activation and ROS production. NADPH oxidase is an enzymatic component of the production of ROS under various pathologic conditions. Activated NADPH oxidase is a multimeric protein consisting of at least three cytosolic subunits: p47phox, p67phox, and p40phox. The p47phox subunit plays a significant role in the acute activation of NADPH oxidase; the phosphorylation of p47phox is thought to inhibit intracellular interactions and promote the binding of p47phox to p22phox, thereby inducing the activation of NADPH oxidase. The expression of phase II and antioxidant enzymes is a defense mechanism that protects tissues from injury by ROS production. The phase II enzymes include the heme oxygenase-1 (HO-1), NADPH quinine oxidoreductase (NQO1), glutathione S-transferase (GST), and superoxide dismutase (SOD). These enzymes are expressed following NRF2 binding to the antioxidant response element (ARE).