Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD. JCI Insight 2017 Jul 20;2(14)
Date
07/21/2017Pubmed ID
28724796Pubmed Central ID
PMC5518565DOI
10.1172/jci.insight.93726Scopus ID
2-s2.0-85033974707 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
Graft-versus-host disease (GVHD) induces pathological damage in peripheral target organs leading to well-characterized, organ-specific clinical manifestations. Patients with GVHD, however, can also have behavioral alterations that affect overall cognitive function, but the extent to which GVHD alters inflammatory and biochemical pathways in the brain remain poorly understood. In the current study, we employed complementary murine GVHD models to demonstrate that alloreactive donor T cells accumulate in the brain and affect a proinflammatory cytokine milieu that is associated with specific behavioral abnormalities. Host IL-6 was identified as a pivotal cytokine mediator, as was host indoleamine 2,3-dioxygenase (IDO-1), which was upregulated in GVHD in an IL-6-dependent manner in microglial cells and was accompanied by dysregulated tryptophan metabolism in the dorsal raphe nucleus and prefrontal cortex. Blockade of the IL-6 signaling pathway significantly reduced donor T cell accumulation, inflammatory cytokine gene expression, and host microglial cell expansion, but did not reverse GVHD-induced tryptophan metabolite dysregulation. Thus, these results indicate that inhibition of IL-6 signaling attenuates neuroinflammation, but does not reverse all of the metabolic abnormalities in the brain during GVHD, which may also have implications for the treatment of neurotoxicity occurring after other T cell-based immune therapies with IL-6-directed approaches.
Author List
Belle L, Zhou V, Stuhr KL, Beatka M, Siebers EM, Knight JM, Lawlor MW, Weaver C, Hashizume M, Hillard CJ, Drobyski WRAuthors
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinCecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Jennifer M. Knight MD, MS Associate Professor in the Psychiatry and Behavioral Medicine department at Medical College of Wisconsin
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin
