Tissue-type plasminogen activator modulates macrophage M2 to M1 phenotypic change through annexin A2-mediated NF-κB pathway

Oncotarget. 2017 Oct 4;8(50):88094-88103. doi: 10.18632/oncotarget.21510. eCollection 2017 Oct 20.

Abstract

Macrophage accumulation is one of the hallmarks of progressive kidney disease. In response to injury, macrophages undergo a phenotypic polarization to become two functionally distinct subsets: M1 and M2 macrophages. Macrophage polarization is a dynamic process, and recent work indicates that macrophages, in response to kidney injury, can shift their polarity. However, the underlying mechanisms remain largely unknown. Tissue-type plasminogen activator (tPA), a protease up-regulated in the chronically injured kidneys, has been shown to preferably promote M1 macrophage accumulation and renal inflammation. We hypothesized that tPA may be an endogenous factor that modulates macrophage M2 to M1 phenotypic change contributing to the accumulation of M1 macrophages in the injured kidneys. It was found that obstruction-induced renal M1 chemokine expression was alleviated in tPA knockout mice, and these knockout mice displayed increased M2 markers. In vitro, resting J774 macrophages were treated with IL-4 to induce M2 phenotype as indicated by de novo expression of arginase 1, Ym1, and IL-10, as well as suppression of iNOS, TNF-α, and IL-1β. Intriguingly, these IL-4-induced M2 macrophages, after tPA treatment, not only lost their M2 markers such as arginase 1, Ym1, and IL-10, but also displayed increased M1 chemokines including iNOS, TNF-α, and IL-1β. Possible endotoxin contamination was also excluded as heat-inactivated tPA lost its effect. Additionally, tPA-mediated macrophage M2 to M1 phenotypic change required its receptor annexin A2, and SN50, a specific NF-κB inhibitor, abolished tPA's effect. Thus, it's clear that tPA promotes macrophage M2 to M1 phenotypic change through annexin A2-mediated NF-κB pathway.

Keywords: M1 macrophages; M2 macrophages; polarity shift; serine protease; tissue-type plasminogen activator.