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

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.

• Authors: 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
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 150 Issue 5 Pg. 1154-1167 (11 2022) ISSN: 1097-6825 [Electronic] United States
• PMID: 35792218 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Inc.

Chemical References

• Interleukin-10
• Interleukin-18
• IL10 protein, mouse

Topics

• Animals
• Mice
• Disease Models, Animal
• Interleukin-10
• Interleukin-18
• Lymphohistiocytosis, Hemophagocytic (pathology)
• Myelopoiesis