3.3 High Mobility Group Box 1 (HMGB1)
HMGB1 is one of the most important damage-associated molecular patters acting as a proinflammatory cytokine [51]. It promotes and perpetuate the immune responses in infectious and non-infectious inflammatory diseases [51,52]. HMGB1 levels were found to be elevated in nasopharyngeal aspirates of hospitalized infants with RSV bronchiolitis, and significantly higher in the moderate-severe group [53]. In immortalized and primary human BECs, the RSV-induced HMGB1 expression was decreased when the cultures were exposed to glycyrrhizin, a specific HMGB1 inhibitor [54]. A dose dependent decreased of the HMGB1 positive cell numbers was also detected, associated with significant reduction in viral replication [54]. In BALB/c mice infected with RSV, type 2 cytokines IL-4, IL-5, and IL-13 were found to be gradually increased in bronchoalveolar lavage from days 14 to 30 post-infection [53]. HMGB1 expression was localized to bronchiolar low columnar/cuboidal cells, found in the small airways. Treatment with anti-HMGB1 antibody significantly reduced HMGB1 levels and IL-4, IL-5, and IL-13 concentrations, suppressed the inflammatory cell infiltration and decreased the severity scores [53]. In IRF7-deficient (-/-) mice, characterized by defective antiviral immunity, infection with PVM (a mouse-specific pathogen belonging to the same genus as RSV) promoted epithelial HMGB1 expression, associated with an increase in the numbers of IL-13-producing ILC2 [55]. Increase of both the levels of the potent airway smooth muscle (ASM) mitogen TGF-β and ASM cell proliferation was also detected, suggesting that ASM alterations could initiate the response to a severe RSV infection in early-life [55]. Anti-HMGB1 antibodies ablated lung ILC2 numbers and ASM growth in vivo , and inhibited ILC2-mediated ASM cell proliferation in a co-culture model [55]. Finally, several other mouse studies using different inducible models of asthma demonstrated that anti-HMGB1 antibody treatment reduced IL-4, IL-5, and IL-13, as well as airway mucus compared to control antibody or mice not given antibody [56,57].