ELV-N34 or RvD6-isomer Counteracts Damaging Astrocyte Phenotypes Protecting the Brain from Omicron BA.5 Sequelae

Abstract

Neurodegenerative diseases induce astrocyte phenotypes that trigger inflammation and cell damage. This cell induction also takes place in post-acute neurological syndrome from SARS-CoV-2 infection. We found that the secretome from Omicron BA.5 infected human nasal epithelial or human lung cells induced the activation of human astrocytes to a reactive pro-inflammatory phenotype as defined by nuclear translocation of NF-kB/p65. Remarkably, the secretome from these cells incubated with Elovanoid (ELV)-N34 or Resolvin D6 (RvD6)-isomer (500nM) did not trigger the formation of reactive astrocytes. One of the factors involved is CXCL1, secreted by Omicron BA.5-infected nasal epithelial cells. So, when CXCL1 was administered intranasally to mice along with Interferon type I, the infiltration of fluorescein indicated a permeabilization of the neurovascular unit. Astrocytes are close to this barrier and contribute to restricting the access of damaging molecules to the brain parenchyma. Together, these results point to a specific way of entry of chemokines and cytokines as part of the secretome from infected cells that may play a role in long COVID brain sequelae.