Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1.
Inflammation resolution is an active process that functions to restore tissue homeostasis. The participation of the plasminogen (Plg)/plasmin (Pla) system in the productive phase of inflammation is well known, but its involvement in the resolution phase remains unclear. Therefore, we aimed to investigate the potential role of Plg/Pla in key events during the resolution of acute inflammation and its underlying mechanisms. Plg/Pla injection into the pleural cavity of BALB/c mice induced a time-dependent influx of mononuclear cells that were primarily macrophages of anti-inflammatory (M2 [F4/80highGr1-CD11bhigh]) and proresolving (Mres [F4/80medCD11blow]) phenotypes, without changing the number of macrophages with a proinflammatory profile (M1 [F4/80lowGr1+CD11bmed]). Pleural injection of Plg/Pla also increased M2 markers (CD206 and arginase-1) and secretory products (transforming growth factor β and interleukin-6) and decreased the expression of inducible nitric oxide synthase (M1 marker). During the resolving phase of lipopolysaccharide (LPS)-induced inflammation when resolving macrophages predominate, we found increased Plg expression and Pla activity, further supporting a link between the Plg/Pla system and key cellular events in resolution. Indeed, Plg or Pla given at the peak of inflammation promoted resolution by decreasing neutrophil numbers and increasing neutrophil apoptosis and efferocytosis in a serine-protease inhibitor-sensitive manner. Next, we confirmed the ability of Plg/Pla to both promote efferocytosis and override the prosurvival effect of LPS via annexin A1. These findings suggest that Plg and Pla regulate several key steps in inflammation resolution, namely, neutrophil apoptosis, macrophage reprogramming, and efferocytosis, which have a major impact on the establishment of an efficient resolution process.
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Postgraduate Program in Pharmaceutical Sciences, School of Pharmacy.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Michelle A
0000-0002-4527-6065
MA
Sugimoto
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.|Postgraduate Program in Clinical and Toxicological Analyses, Department of Clinical and Toxicological Analyses, School of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Ana Luíza C
ALC
Ribeiro
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.|Postgraduate Program in Clinical and Toxicological Analyses, Department of Clinical and Toxicological Analyses, School of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Bruno R C
0000-0002-9561-7606
BRC
Costa
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Juliana P
0000-0001-8188-3738
JP
Vago
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Kátia M
KM
Lima
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Fernanda S
0000-0002-5776-1519
FS
Carneiro
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Mylena Maira O
MMO
Ortiz
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Graziele Letícia N
0000-0001-7212-6006
GLN
Lima
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Aline A F
0000-0001-8649-3966
AAF
Carmo
Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Renata M
0000-0001-9753-302X
RM
Rocha
Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Denise A
DA
Perez
Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Alessandra C
0000-0002-8912-5904
AC
Reis
Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Vanessa
0000-0003-1038-2324
V
Pinho
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA; and.
Lindsey A
LA
Miles
Laboratory of Respiratory Viruses and Measles, Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
Cristiana C
0000-0002-4400-9141
CC
Garcia
Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.
Mauro M
0000-0002-6944-3008
MM
Teixeira
Signaling in Inflammation Laboratory, Department of Clinical and Toxicological Analyses.|Postgraduate Program in Pharmaceutical Sciences, School of Pharmacy.|Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, and.|Postgraduate Program in Clinical and Toxicological Analyses, Department of Clinical and Toxicological Analyses, School of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Lirlândia P
0000-0002-1042-9762
LP
Sousa
D000208:Acute Disease; D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D065150:Cellular Reprogramming; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D000067996:RAW 264.7 Cells
D017305:Annexin A1; D000943:Antigens, Differentiation; D008070:Lipopolysaccharides; C573274:annexin A1, mouse; D010958:Plasminogen; D005341:Fibrinolysin