Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses

• Published in: Immunobiology (1979) 2019-09, Vol.224 (5), p.672-680
• Main Authors: Sumanth, Mosale Seetharam, Abhilasha, Kandahalli Venkataranganayaka, Jacob, Shancy Petsel, Chaithra, Vyala Hanumanthareddy, Basrur, Venkatesha, Willard, Belinda, McIntyre, Thomas M., Prabhu, K. Sandeep, Marathe, Gopal K.
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - metabolism; Alpha-1-acid glycoprotein; Animals; Cell Adhesion - genetics; Cell Adhesion - immunology; Endotoxemia; Endotoxemia - etiology; Endotoxemia - metabolism; Endotoxemia - mortality; Female; Inflammation; Inflammation - etiology; Inflammation - metabolism; Lipopolysaccharides - immunology; Lipoproteins - metabolism; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Male; MAP Kinase Signaling System; MAP kinases; Mice; Models, Biological; Neutrophil adhesion; Neutrophils - immunology; Neutrophils - metabolism; Orosomucoid - isolation & purification; Orosomucoid - metabolism; Signal Transduction - drug effects; TLRs; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2019.06.003

[Display omitted] •This is the very first study that shows the modulatory effects exerted by the alpha-1-acid glycoprotein (AGP-1) on bacterial endotoxemia.•AGP-1 shows selective augmentation of the TLR-2 – mediated responses but not TLR-4 – mediated responses both in vivo and in vitro.•Blunting TLR-2 along with TLR-4 responses may be studied seriously while targeting sepsis.•Consideration of involvement of endogenous proteins in sepsis needs to be revisited. Alpha-1-acid glycoprotein (AGP-1) is a major positive acute phase glycoprotein with unknown functions that likely play a role in inflammation. We tested its involvement in a variety of inflammatory responses using human AGP-1 purified to apparent homogeneity and confirmed its identity by immunoblotting and mass spectrometry. AGP-1 alone upregulated MAPK signaling in murine peritoneal macrophages. However, when given in combination with TLR ligands, AGP-1 selectively augmented MAPK activation induced by ligands of TLR-2 (Braun lipoprotein) but not TLR-4 (lipopolysaccharide). In vivo treatment of AGP-1 in a murine model of sepsis with or without TLR-2 or TLR-4 ligands, selectively potentiated TLR-2-mediated mortality, but was without significant effect on TLR-4-mediated mortality. Furthermore, in vitro, AGP-1 selectively potentiated TLR-2 mediated adhesion of human primary immune cell, neutrophils. Hence, our studies highlight a new role for the acute phase protein AGP-1 in sepsis via its interaction with TLR-2 signaling mechanisms to selectively promote responsiveness to one of the two major gram-negative endotoxins, contributing to the complicated pathobiology of sepsis.