Proinflammatory Effects of Respiratory Syncytial Virus–Induced Epithelial HMGB1 on Human Innate Immune Cell Activation

Kempaiah Rayavara, Alexander Kurosky, Susan J. Stafford, Nisha J. Garg,Allan R. Brasier, Roberto P. Garofalo, and Yashoda M. Hosakote, J Immunol 2018; 201:2753-2766; Prepublished online 1 October 2018;
doi: 10.4049/jimmunol.1800558


The first epithelial molecular events upon infection define the size and direction of the inflammatory response, which ultimately defines disease in RSV infected patients. Rayavara and colleagues shed a light on this complex process. Previously, this group showed that RSV promotes the release of high mobility group box 1 (HMGB1) by airway epithelial cells. HMGB1 is a nuclear protein, which becomes an alarmin after secretion to the extracellular space to induce an inflammatory response.
In the current study they show, that HMGB1 forms a link between the infected respiratory epithelium and the response by immune cells. After RSV infection, HMGB1 is expressed by airway epithelial cells. This process is dependent on TLR4 and is mediated by the MAPK and NF-kB pathway. Blocking of TLR4 or the NF-kB pathway in AECs, decreases the expression of HMGB1. Next they show that HMGB1 stimulates primary immune cells, such as monocytes and macrophages, to produce inflammatory cytokines and chemokines.
Blocking the HMGB1 pathway, under an umbrella of antiviral treatment, might limit immune pathology and thereby ameliorate the course of disease in children with RSV infection.

Abstract on PubMed