Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease

Saborni Chakraborty, Bowie Yik Ling Cheng, Desmond L. Edwards, Joseph C. Gonzalez, David Kung Chun Chiu, Hong Zheng, Courtney Scallan, Xinrong Guo, Gene S. Tan, Greg P. Coffey, Pamela B. Conley, Patrick S. Hume, William J. Janssen, Derek E. Byers, Philip A. Mudd, Jeffery Taubenberger, Matthew Memoli, Mark M. Davis, Katrin F. Chua, Michael S. DiamondEvangelos Andreakos, Purvesh Khatri, Taia T. Wang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.

Original languageEnglish
Pages (from-to)182-196.e10
JournalImmunity
Volume58
Issue number1
DOIs
StatePublished - Jan 14 2025

Keywords

  • CD209
  • IgG glycosylation
  • IgG sialylation
  • RE1-silencing transcription factor
  • REST
  • airway inflammation
  • alveolar macrophage
  • antibody signaling
  • influenza immunity

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