title: Tissue-type plasminogen activator (tPA) promotes M1 macrophage survival through p90 ribosomal S6 kinase (RSK) and p38 mitogen-activated protein kinase (MAPK) pathway.
abstract: Macrophage accumulation is one of the hallmarks of progressive kidney disease. Resting macrophages have a finite lifespan, but become resistant to apoptosis in response to pathogenic cues, whereas the underlying mechanism remains unknown. Tissue-type plasminogen activator (tPA), a protease up-regulated in the kidneys with chronic injury, has been shown to promote macrophage accumulation and renal inflammation. We hypothesized that tPA may be the endogenous factor that promotes macrophage survival and extends their lifespan that leads to their accumulation in the injured kidneys. We examined the role of tPA in macrophage survival, and found that tPA protected macrophages from both staurosporine and H2O2-induced apoptosis. tPA promoted the survival of both resting and lipopolysaccharide- or interferon-γ-induced M1 macrophages, but failed to do so in the interleukin 4 (IL4)-induced M2 macrophages. In the kidneys with unilateral ureteral obstruction, there were significantly more apoptotic M1 macrophages in tPA-deficient mice than their wild-type counterparts, and obstruction-induced M1 macrophages accumulation and M1 chemokine expression were markedly reduced in these knock-out mice. The cytoprotective effect of tPA required its receptor, LDL receptor-related protein-1 (LRP-1). tPA induced the phosphorylation of Erk1/2, p90 ribosomal S6 kinase (RSK), and p38 in a temporal order. The tPA-mediated macrophage survival was eliminated by PD98059, BI-D1870, or sc68376, the specific inhibitors for Erk1/2, p90RSK, or p38, respectively. Thus, it is clear that tPA promoted M1 macrophage survival through its receptor LRP-1-mediated novel signaling cascade involving Erk1/2, p90RSK, and p38, which leads to the accumulation of these cells in the injured kidneys.
authors: From the Department of Medicine, Division of Nephrology, Penn State University College of Medicine, Hershey, Pennsylvania 17033 and.
authors: Ling
authors: L
authors: Lin
authors: the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Yang
authors: Y
authors: Jin
authors: From the Department of Medicine, Division of Nephrology, Penn State University College of Medicine, Hershey, Pennsylvania 17033 and kebinhu@hmc.psu.edu.
authors: Kebin
authors: K
authors: Hu
mesh_terms: D000818:Animals; D002460:Cell Line; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D019893:Ribosomal Protein S6 Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator
keywords: Apoptosis; Cell Signaling; Macrophage; Serine Protease; Tissue Plasminogen Activator (tPA)