Excessive IL-10 and IL-18 trigger hemophagocytic lymphohistiocytosis–like hyperinflammation and enhanced myelopoiesis
Journal of Allergy and Clinical Immunology(2022)
摘要
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. To explore this, we analyzed plasma cytokine profiles of 87 secondary HLH patients and found significant co-elevation of IL-10 and IL-18 was a prominent feature. By co-expressing excessive circulating IL-10 and IL-18 in mice, we demonstrated that the two cytokines triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes, driving peripheral lymphopenia, neutrophilia, and monocytosis; bone marrow hematopoiesis showed a striking shift toward enhanced myelopoiesis. Further, IL-10 combined with IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid-cell-recruiting chemokines (CCL2, CCL3, CCL7). Transcriptional characterization suggested the IL-10/IL-18-mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome pathway activation in macrophages. Notably, IL-10 blockade protected against the lethal disease in HLH mouse models. Together, these findings provide mechanistic insights on the pathogenesis of hyperinflammation and the development of new therapeutics.
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关键词
IL-10,IL-18,hyperinflammation,HLH,macrophage polarization,myelopoiesis,cytokine storm
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