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

Kempaiah Rayavara, Alexander Kurosky, Susan J. Stafford, Nisha Garg, Allan R. Brasier, Roberto Garofalo, Yashoda Hosakote Madaiah

Research output: Contribution to journalArticle

Abstract

High mobility group box 1 (HMGB1) is a multifunctional nuclear protein that translocates to the cytoplasm and is subsequently released to the extracellular space during infection and injury. Once released, it acts as a damage-associated molecular pattern and regulates immune and inflammatory responses. Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants and elderly, for which no effective treatment or vaccine is currently available. This study investigated the effects of HMGB1 on cytokine secretion, as well as the involvement of NF-κB and TLR4 pathways in RSV-induced HMGB1 release in human airway epithelial cells (AECs) and its proinflammatory effects on several human primary immune cells. Purified HMGB1 was incubated with AECs (A549 and small alveolar epithelial cells) and various immune cells and measured the release of proinflammatory mediators and the activation of NF-κB and P38 MAPK. HMGB1 treatment significantly increased the phosphorylation of NF-κB and P38 MAPK but did not induce the release of cytokines/chemokines from AECs. However, addition of HMGB1 to immune cells did significantly induce the release of cytokines/chemokines and activated the NF-κB and P38 MAPK pathways. We found that activation of NF-κB accounted for RSV-induced HMGB1 secretion in AECs in a TLR4-dependent manner. These results indicated that HMGB1 secreted from AECs can facilitate the secretion of proinflammatory mediators from immune cells in a paracrine mechanism, thus promoting the inflammatory response that contributes to RSV pathogenesis. Therefore, blocking the proinflammatory function of HMGB1 may be an effective approach for developing novel therapeutics.

Original languageEnglish (US)
Pages (from-to)2753-2766
Number of pages14
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume201
Issue number9
DOIs
StatePublished - Nov 1 2018

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Respiratory Syncytial Viruses
p38 Mitogen-Activated Protein Kinases
Epithelial Cells
Cytokines
Chemokines
Alveolar Epithelial Cells
Extracellular Space
Nuclear Proteins
Respiratory Tract Infections
Cytoplasm
Therapeutics
Vaccines
Phosphorylation
Wounds and Injuries
Infection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Proinflammatory Effects of Respiratory Syncytial Virus-Induced Epithelial HMGB1 on Human Innate Immune Cell Activation. / Rayavara, Kempaiah; Kurosky, Alexander; Stafford, Susan J.; Garg, Nisha; Brasier, Allan R.; Garofalo, Roberto; Hosakote Madaiah, Yashoda.

In: Journal of immunology (Baltimore, Md. : 1950), Vol. 201, No. 9, 01.11.2018, p. 2753-2766.

Research output: Contribution to journalArticle

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