A group from Gazi University Hospital, Medical Faculty, Besevler, Ankara, Turkey, etc. has first reported that HMGB1 released from respiratory infection in COVID-19 stimulates trigeminal neurons and causes COVID-19 headache.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358545/
COVID-19 patients suffered from headache had significantly higher serum levels of HMGB1, NLRP3, ACE2, and IL-6 than COVID-19 patients without headache, whereas CGRP and IL-10 levels were similar in the groups.
Taken all the data together, it was suggested that HMGB1 as a potent proinflammatory molecule with nociceptive properties would be a central player in proinflammatory reactions during SARS-Co-V2 infection and induce headache through activation of trigeminal neurons.
Extracellular HMGB1 is secreted from activated macrophages, monocytes natural killer cells and dendritic cells in response to pathogen invasion such as SARS-CoV-2. Neurons, astrocytes, microglia, and endothelial cells are also able to actively secrete HMGB1 after exposure to cytokines, interferons, etc. Furthermore, cell injury and necrotic process caused by ARDS of COVID-19 can greatly contribute to increase of serum levels of HMGB1.