Autophagy Receptor p62 Regulates SARS-CoV-2-Induced Inflammation in COVID-19

• Published in: Cells (Basel, Switzerland) Switzerland), 2023-04, Vol.12 (9), p.1282
• Main Authors: Paunovic, Verica, Vucicevic, Ljubica, Misirkic Marjanovic, Maja, Perovic, Vladimir, Ristic, Biljana, Bosnjak, Mihajlo, Mandic, Milos, Stevanovic, Danijela, Harhaji-Trajkovic, Ljubica, Lalosevic, Jovan, Nikolic, Milos, Bonaci-Nikolic, Branka, Trajkovic, Vladimir
• Format: Article
• Language: English
• Subjects: Analysis; Anticoagulants; Antigen presentation; Antiviral agents; Autophagy; Autophagy (Cytology); Care and treatment; Cell culture; Coronaviruses; COVID-19; COVID-19 - pathology; Cytokines; Dosage and administration; Enzyme-linked immunosorbent assay; Flow cytometry; Health aspects; Humans; IL-1β; Immunostimulation; Immunosuppression; Inflammation; Inflammation - metabolism; Interleukin 10; Interleukin 17; Interleukin 6; Interleukin 8; Interleukin-10 - blood; Interleukin-17 - blood; Interleukin-33 - blood; Interleukin-6 - blood; Leukocytes; Monocytes; mRNA; NSP; ORF3a; Oxygen therapy; p62; Plasma; Pneumonia; Proteins; RNA, Messenger; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Software; Tumor necrosis factor; Tumor necrosis factor-TNF; α-Interferon; γ-Interferon
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12091282

As autophagy can promote or inhibit inflammation, we examined autophagy-inflammation interplay in COVID-19. Autophagy markers in the blood of 19 control subjects and 26 COVID-19 patients at hospital admission and one week later were measured by ELISA, while cytokine levels were examined by flow cytometric bead immunoassay. The antiviral IFN-α and proinflammatory TNF, IL-6, IL-8, IL-17, IL-33, and IFN-γ were elevated in COVID-19 patients at both time points, while IL-10 and IL-1β were increased at admission and one week later, respectively. Autophagy markers LC3 and ATG5 were unaltered in COVID-19. In contrast, the concentration of autophagic cargo receptor p62 was significantly lower and positively correlated with TNF, IL-10, IL-17, and IL-33 at hospital admission, returning to normal levels after one week. The expression of SARS-CoV-2 proteins NSP5 or ORF3a in THP-1 monocytes caused an autophagy-independent decrease or autophagy-inhibition-dependent increase, respectively, of intracellular/secreted p62, as confirmed by immunoblot/ELISA. This was associated with an NSP5-mediated decrease in TNF/IL-10 mRNA and an ORF3a-mediated increase in TNF/IL-1β/IL-6/IL-10/IL-33 mRNA levels. A genetic knockdown of p62 mimicked the immunosuppressive effect of NSP5, and a p62 increase in autophagy-deficient cells mirrored the immunostimulatory action of ORF3a. In conclusion, the proinflammatory autophagy receptor p62 is reduced inacute COVID-19, and the balance between autophagy-independent decrease and autophagy blockade-dependent increase of p62 levels could affect SARS-CoV-induced inflammation.