Excessive IL-10 and IL-18 trigger hemophagocytic lymphohistiocytosis–like hyperinflammation and enhanced myelopoiesis

Yuting Tang, Qian Xu, Hui Luo, Xiaomei Yan, Gaoxiang Wang, Liang Hu, Jin Jin, David P. Witte, Rebecca A. Marsh, Liang Huang, Gang Huang, Jianfeng Zhou

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Hyperinflammation is a life-threatening condition associated with various clinical disorders characterized by excessive immune activation and tissue damage. Multiple cytokines promote the development of hyperinflammation; however, the contribution of IL-10 remains unclear despite emerging speculations for a pathological role. Clinical observations from hemophagocytic lymphohistiocytosis (HLH), a prototypical hyperinflammatory disease, suggest that IL-18 and IL-10 may collectively promote the onset of a hyperinflammatory state. Objective: We aimed to investigate the collaborative roles of IL-10 and IL-18 in hyperinflammation. Methods: A comprehensive plasma cytokine profile for 87 secondary HLH patients was first depicted and analyzed. We then investigated the systemic and cellular effects of coelevated IL-10 and IL-18 in a transgenic mouse model and cultured macrophages. Single-cell RNA sequencing was performed on the monocytes/macrophages isolated from secondary HLH patients to explore the clinical relevance of IL-10/IL-18–mediated cellular signatures. The therapeutic efficacy of IL-10 blockade was tested in HLH mouse models. Results: Excessive circulating IL-10 and IL-18 triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes in mice, driving peripheral lymphopenia and a striking shift toward enhanced myelopoiesis in the bone marrow. IL-10 and IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid cell–recruiting chemokines. Transcriptional characterization suggested the IL-10/IL-18–mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome activation in macrophages. IL-10 blockade protected against the lethal disease in HLH mouse models. Conclusion: Coelevated IL-10 and IL-18 are sufficient to drive HLH-like hyperinflammatory syndrome, and blocking IL-10 is protective in HLH models.

Original languageEnglish (US)
Pages (from-to)1154-1167
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume150
Issue number5
DOIs
StatePublished - Nov 2022
Externally publishedYes

Keywords

  • HLH
  • IL-10
  • IL-18
  • cytokine storm
  • hyperinflammation
  • macrophage polarization
  • myelopoiesis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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