Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase

Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brai...

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Vydáno v:	PLoS pathogens Ročník 12; číslo 5; s. e1005615
Hlavní autoři:	Huang, Lei, Ou, Rong, Rabelo de Souza, Guilherme, Cunha, Thiago M., Lemos, Henrique, Mohamed, Eslam, Li, Lingqian, Pacholczyk, Gabriela, Randall, Janice, Munn, David H., Mellor, Andrew L.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.05.2016 Public Library of Science (PLoS)
Témata:	Animals Biology and Life Sciences Brain research Cytokines Disease Models, Animal Enzymes Experiments Flow Cytometry Genetic aspects Health aspects HIV Human immunodeficiency virus Hyperalgesia - enzymology Hyperalgesia - etiology Hypersensitivity Hypotheses Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis Infections Inflammation Influenza Influenza A virus Kynurenine - metabolism Laboratory animals Leukemia Medicine and Health Sciences Mice Orthomyxoviridae Pain Pain management Physiological aspects Polymerase Chain Reaction Research and Analysis Methods Retroviridae Rodents Spinal cord Spleen Tryptophan Virus diseases Virus Diseases - complications Viruses
ISSN:	1553-7374, 1553-7366, 1553-7374
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Shrnutí:	Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. Conceived and designed the experiments: LH GRdS ALM. Performed the experiments: LH RO GRdS HL EM LL GP JR. Analyzed the data: LH RO GRdS TMC HL EM LL DHM ALM. Wrote the paper: LH TMC DHM ALM. I have read the journal's policy and the authors of this manuscript have the following competing interests: ALM and DHM serve as consultants for NewLink Genetics Inc. and receive remuneration from this source. The authors declare no additional competing financial interests. This does not alter our adherence to all PLOS policies on sharing data and materials.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1005615