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

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.

TREM-1 Modulation Strategies for Sepsis

“…N1 is a 10-aa inhibitory peptide based on the N-terminal aa sequence (aa 77–86) of PGLYRP1 ( 80 ). Using affinity chromatography, N1 was shown to bind sTREM-1 immobilized on CNBr-activated Sepharose ( 80 ).…”

“…N1 is a 10-aa inhibitory peptide based on the N-terminal aa sequence (aa 77–86) of PGLYRP1 ( 80 ). Using affinity chromatography, N1 was shown to bind sTREM-1 immobilized on CNBr-activated Sepharose ( 80 ). Using immunoblotting, N1 was also shown to bind TREM-1 on the surface of monocytes ( 80 ) ( Figure 1 ).…”

“…Using affinity chromatography, N1 was shown to bind sTREM-1 immobilized on CNBr-activated Sepharose ( 80 ). Using immunoblotting, N1 was also shown to bind TREM-1 on the surface of monocytes ( 80 ) ( Figure 1 ). Monocytes and lymphocytes exposed to PGLYRP1 and Hsp70, two previously mentioned ligands of TREM-1, had decreased LDH release in the presence of N1.…”

N-Terminal Peptide of PGLYRP1/Tag7 Is a Novel Ligand for TREM-1 Receptor

“…Our previous studies defined peptides of Tag7 with an ability to decrease inflammation in mice caused by acute lung injury (ALI) [ 34 ]. These peptides are located in opposite parts of the Tag7 protein and bind to different receptors.…”

“…C-terminal peptides of Tag7 called 17.1 and 17.1A interact with TNFR-1, and the N-terminal peptide of Tag7, named N1, binds to the TREM-1 receptor. These peptides blocked signaling pathways from these receptors and reduced inflammation in both in vivo and in vitro experiments [ 34 , 35 , 36 ].…”