Protein PGLYRP1/Tag7 Peptides Decrease the Proinflammatory Response in Human Blood Cells and Mouse Model of Diffuse Alveolar Damage of Lung through Blockage of the TREM-1 and TNFR1 Receptors.

Tatiana N Sharapova,Vitaly A Kazakov,Anna A Kudriaeva,Georgii B Telegin,Elena A Romanova,Alexey A Belogurov,Denis V Yashin,Lidia P Sashchenko,Alexey N Minakov,Olga K Ivanova,Aleksandr S Chernov,Alexander G Gabibov

doi:10.3390/ijms222011213

Abstract

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as “cytokine storm”, which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.

Highlights

The following goals were achieved: (1) A new peptide of innate immunity protein Tag7 was identified; N1 is located on the molecule N-terminus, capable of binding to the receptor triggering receptor expressed on myeloid cells-1 (TREM-1) and inhibiting its activation
(2) A new function of N-terminal peptides and the previously described C-terminal peptides of Tag7 was elucidated, i.e., their capability to inhibit the expression of proinflammatory cytokines in human immune cells ex vivo and in a mouse model of acute lung injury (ALI) in vivo
We have demonstrated that the Tag7 molecule has two sites that bind to its receptors

Summary

Introduction

Proinflammatory cytokines are crucial during the activation of the immune system. The overproduction of proinflammatory cytokines associated with different alterations in the immune response can cause severe negative consequences such as tissue destruction in autoimmune arthritis or the development of septic shock and acute respiratory distress syndrome (ARDS) [1,2,3]. The infection caused by SARS-CoV-2 is accompanied by the release of a large number of proinflammatory cytokines in an event known as “cytokine storm”. A too strong proinflammatory response seen in cytokine storm is similar to septic shock as regards the inducing mechanisms. It contributes to the severe clinical course and high fatality rates in patients infected with the SARS-CoV-2 and Ebola viruses [4]

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