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Contributed by Ruslan Medzhitov, December 11, 2018 (sent for review December 5, 2018; reviewed by Ajay Chawla and Tadatsugu Taniguchi)
Significance
Adult secondary hemophagocytic lymphohistiocytosis (sHLH) is a fulminant hyperinflammatory syndrome with mortality exceeding 80% in spite of state-of-the-art medical care. The pathogenesis of sHLH, unlike primary HLH, which is primarily genetic, is poorly understood. Here we describe a model of sHLH that recapitulates many aspects of human sHLH. We found that the hyperinflammation in this model is macrophage intrinsic and identified a unique transcriptional profile associated with sHLH macrophages that was also present in patients with sHLH. We also found that these hyperinflammatory macrophages were highly dependent on glycolytic metabolism. Consequently, we found that administration of the glycolysis inhibitor 2-deoxyglucose was sufficient to rescue animals with sHLH by significantly suppressing the inflammatory response.
Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a highly mortal complication associated with sepsis. In adults, it is often seen in the setting of infections, especially viral infections, but the mechanisms that underlie pathogenesis are unknown. sHLH is characterized by a hyperinflammatory state and the presence hemophagocytosis. We found that sequential challenging of mice with a nonlethal dose of viral toll-like receptor (TLR) agonist followed by a nonlethal dose of TLR4 agonist, but not other permutations, produced a highly lethal state that recapitulates many aspects of human HLH. We found that this hyperinflammatory response could be recapitulated in vitro in bone marrow-derived macrophages. RNA sequencing analyses revealed dramatic up-regulation of the red-pulp macrophage lineage-defining transcription factor SpiC and its associated transcriptional program, which was also present in bone marrow macrophages sorted from patients with sHLH. Transcriptional profiling also revealed a unique metabolic transcriptional profile in these macrophages, and immunometabolic phenotyping revealed impaired mitochondrial function and oxidative metabolism and a reliance on glycolytic metabolism. Subsequently, we show that therapeutic administration of the glycolysis inhibitor 2-deoxyglucose was sufficient to rescue animals from HLH. Together, these data identify a potential mechanism for the pathogenesis of sHLH and a potentially useful therapeutic strategy for its treatment.
Footnotes
- ↵1To whom correspondence may be addressed. Email: andrew.wang{at}yale.edu or ruslan.medzhitov{at}yale.edu.
Author contributions: A.W. and R.M. designed research; A.W., S.D.P., J.S.W., S.Y., C.Z., and C.J.B. performed research; A.W., C.J.B., and R.M. analyzed data; and A.W. and R.M. wrote the paper.
Reviewers: A.C., University of California, San Francisco; and T.T., University of Tokyo.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (accession no. GSE124765).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820704116/-/DCSupplemental.
Published under the PNAS license.
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Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice
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