Polymerized type I collagen down-regulates STAT-1 phosphorylation through engagement to LAIR-1 in M1-macrophages avoiding long COVID

BackgroundThe polymerized type I collagen (PTIC) is a {gamma}-irradiated mixture of pepsinized porcine type I collagen and polyvinylpyrrolidone (PVP). It has immunomodulatory properties. However, the receptor and signaling pathway through which it exerts its therapeutic effects has not yet been identified. AimTo evaluate LAIR-1 as a potential receptor for PTIC and the signaling pathway evoked by ligand-receptor binding. MethodsLAIR-1 binding assay was performed by incubating various concentrations of recombinant human LAIR-1 with native type I collagen or PTIC. Macrophages M1- derived from THP-1 cells were cultured with 2-10% PTIC for 24 h. Cell lysates from THP- 1, monocytes-like cells (MLCs), M1, M1+IFN-{gamma}, M1+LPS, and 2 or 10% PTIC treated M1 were analyzed by western blot for the transcription factors NF-{kappa}B (p65), p38, STAT-1, and pSTAT-1. Cytokines, Th1 cells, and M1/M2 macrophages were analyzed by luminometry and flow cytometry from blood samples of symptomatic COVID-19 outpatients on treatment with intramuscular administration of PTIC. ResultsPTIC binds LAIR-1 with a similar affinity to native collagen. This binding decreases STAT-1 signaling IFN-{gamma}-induced and IL-1{beta} expression in M1 macrophages by down-regulating STAT-1 phosphorylation. Moreover, intramuscular PTIC treatment of symptomatic COVID-19 outpatients decreased at statistically significant levels the percentage of M1 macrophages and cytokines (IP-10, MIF, eotaxin, IL-8, IL-1RA, and M- CSF) associated with STAT-1 transcription factor and increased M2 macrophages and Th1 cells. The downregulation of inflammatory mediators was related to better oxygen saturation and decreased dyspnea, chest pain, cough, and chronic fatigue syndrome in the acute phase of infection and the long term. ConclusionPTIC is an agonist of LAIR-1 and down-regulates STAT-1 phosphorylation. PTIC could be relevant for treating STAT-1-mediated inflammatory diseases, including COVID-19 and long COVID