Tissue-type plasminogen activator (tPA) is the major intravascular activator of fibrinolysis and a ligand for receptors involved in cell-signaling. In cultured macrophages, tPA inhibits the response to lipopolysaccharide (LPS) by a pathway that apparently requires LDL Receptor-related Protein-1 (LRP1). Herein, we show that the mechanism by which tPA neutralizes LPS involves rapid reversal of IκBα phosphorylation. tPA independently induced transient IκBα phosphorylation and ERK1/2 activation in macrophages; however, these events that did not trigger inflammatory mediator expression. The tPA signaling response was distinguished from the signature of signaling events elicited by pro-inflammatory LRP1 ligands, such as Receptor-associated Protein (RAP), which included sustained IκBα phosphorylation and activation of all three MAP kinases (ERK1/2, c-Jun kinase, and p38 MAP kinase). Enzymatically-active and inactive tPA demonstrated similar immune modulatory activity. Intravascular administration of enzymatically-inactive tPA in mice blocked the toxicity of LPS. In mice not treated with exogenous tPA, the plasma concentration of endogenous tPA increased 3-fold in response to LPS, to 116±15 pM, but remained below the approximate threshold for eliciting anti-inflammatory cell-signaling in macrophages (~2.0 nM). This threshold is readily achieved in patients when tPA is administered therapeutically for stroke. In addition to LRP1, we demonstrate that the N-Methyl-d-Aspartic acid Receptor (NMDA-R) is expressed by macrophages and essential for anti-inflammatory cell-signaling and regulation of cytokine expression by tPA. The NMDA-R and Toll-like Receptor-4 were not required for pro-inflammatory RAP-signaling. By mediating the tPA response in macrophages, the NMDA-R provides a pathway by which the fibrinolysis system may regulate innate immunity.
Tissue-type Plasminogen Activator Regulates Macrophage Activation and Innate Immunity / Mantuano, Elisabetta; Azmoon, Pardis; Brifault, Coralie; Banki, Michael A; Gilder, Andrew S; Campana, Wendy M; Gonias, Steven L. - In: BLOOD. - ISSN 0006-4971. - 11:130(2017), pp. 1364-1374. [10.1182/blood-2017-04-780205]
|Titolo:||Tissue-type Plasminogen Activator Regulates Macrophage Activation and Innate Immunity|
MANTUANO, ELISABETTA (Primo)
|Data di pubblicazione:||2017|
|Citazione:||Tissue-type Plasminogen Activator Regulates Macrophage Activation and Innate Immunity / Mantuano, Elisabetta; Azmoon, Pardis; Brifault, Coralie; Banki, Michael A; Gilder, Andrew S; Campana, Wendy M; Gonias, Steven L. - In: BLOOD. - ISSN 0006-4971. - 11:130(2017), pp. 1364-1374. [10.1182/blood-2017-04-780205]|
|Appartiene alla tipologia:||01a Articolo in rivista|