The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells

Ashraf S. Yousif, Larance Ronsard, Pankaj Shah, Tatsushi Omatsu, Maya Sangesland, Thalia Bracamonte Moreno, Evan C. Lam, Vladimir D. Vrbanac, Alejandro B. Balazs, Hans Christian Reinecker, Daniel Lingwood

Research output: Contribution to journalArticlepeer-review

Abstract

The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions. Hyper-elevated IL-6 underscores cytokine storming and chronic inflammatory disorders. Yousif et al. demonstrate that conventional dendritic cells are a major source of sIL-6R, which forms a buffer system that sets the in-solution persistence of IL-6, regulating inflammatory immune reactions.

Original languageEnglish (US)
Pages (from-to)235-246.e5
JournalImmunity
Volume54
Issue number2
DOIs
StatePublished - Feb 9 2021

Keywords

  • antibody response
  • immune defense
  • inflammation
  • regulation
  • signaling

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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