Journal Article

The specialized pro-resolving lipid mediator Protectin D1 affects macrophages differentiation and activity in Adult-onset Still’s disease and COVID-19, two hyperinflammatory diseases sharing similar transcriptomic profiles

Luca Navarini, Amelia Rigon, Alessandro Leuti, Marina Fava, Alessia Mattei, Luisa Arcarese, Ilenia Di Cola, Erika Corberi, Silvia Angeletti, Federica Sambuco, Onorina Berardicurti, Mauro Maccarrone, Annalisa Marino, Marta Fogolari, Francesco Travaglino, Paola Cipriani, Damiano Currado, Annamaria Iagnocco, Francesco Ursini, Erminia Mariani, Pietro Bearzi, Felice Eugenio Agrò, Alice Biaggi, Piero Ruscitti, Raffaele Antonelli Incalzi, Roberto Giacomelli, Marta Vomero

2023

Overview

COVID-19 and autoinflammatory diseases, such as Adult-onset Still's Disease (AOSD), are characterized by hyperinflammation, in which it is observed massive production and uncontrolled secretion of pro-inflammatory cytokines. The specialized pro-resolving lipid mediators (SPMs) family is one the most important processes counteracting hyperinflammation inducing tissue repair and homeostasis restoration. Among SPMs, Protectin D1 (PD1) is able to exert antiviral features, at least in animal models. The aim of this study was to compare the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with AOSD and COVID-19 and to evaluate the role of PD1 on those diseases, especially in modulating macrophages polarization. This study enrolled patients with AOSD, COVID-19, and healthy donors HDs, undergoing clinical assessment and blood sample collection. Next-generation deep sequencing was performed to identify differences in PBMCs transcripts profiles. Plasma levels of PD1 were assessed by commercial ELISA kits. Monocyte-derived macrophages were polarized into M1 and M2 phenotypes. We analyzed the effect of PD1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays. In the transcriptomes from AOSD patients and COVID-19 patients, genes involved in inflammation, lipid catabolism, and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Patients affected by COVID-19, hospitalized in intensive care unit (ICU), showed higher levels of PD1 when compared to not-ICU hospitalized patients and HDs (ICU COVID-19 vs not-ICU COVID-19, p= 0.02; HDs vs ICU COVID-19, p= 0.0006). PD1 levels were increased in AOSD patients with SS ≥1 compared to patients with SS=0 (p=0.028) and HDs (p=0.048). treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p<0.05). Furthermore, a significant release of IL-10 and MIP-1β from M2 macrophages was observed when compared to controls (p<0.05). PD1 is able to induce pro-resolutory programs in both AOSD and COVID-19 increasing M2 polarization and inducing their activity. In particular, PD1-treated M2 macrophages from AOSD and COVID-19 patients increased the production of IL-10 and enhanced homeostatic restoration through MIP-1β production.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Adult-onset Still’s Disease / Adult-onset Still’s Disease; COVID-19; hyperinflammation; protectin D1; specialized pro-resolving mediators (SPMs) / Animal models / Arthritis / Cell activation / Cell Differentiation / Cell Differentiation - genetics / Chemokine CCL4 / Chemokine CCL4 - metabolism / Chemokines / Chronic illnesses / COVID-19 / COVID-19 - metabolism / Cytokines / Cytokines - metabolism / Disease / Docosahexaenoic Acids / Docosahexaenoic Acids - metabolism / Enzyme-linked immunosorbent assay / Flow cytometry / Genotype & phenotype / Homeostasis / Humans / hyperinflammation / Immunologic diseases. Allergy / Immunology / Inflammation / Inflammatory diseases / Interleukin 10 / Interleukin-10 - metabolism / Leukocytes, Mononuclear / Leukocytes, Mononuclear - metabolism / Lipid metabolism / Macrophages / Medical prognosis / Monocytes / Patients / PD-1 protein / Peripheral blood mononuclear cells / Phenotypes / Plasma levels / Polarization / protectin D1 / RC581-607 / Severe acute respiratory syndrome coronavirus 2 / Software / specialized pro-resolving mediators (SPMs) / Still's Disease, Adult-Onset / Transcriptome / Transcriptomes / Transcriptomics