IL-33 signaling is essential to attenuate viral-induced encephalitis development by downregulating iNOS expression in the central nervous system

Abstract

BackgroundViral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection.MethodsWild-type (WT), ST2 (ST2−/−), and nitric oxide synthase-deficient mice (iNOS−/−) and Stat6 (Stat6−/−)-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells.ResultsWe have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2−/− mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS−/− mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology.ConclusionsWe provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-γ modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0628-1) contains supplementary material, which is available to authorized users.

Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy

“…In addition, IL-33 was also reported to be essential to attenuate viral-induced encephalitis [41]. In line with these reports, enhanced expression of IL-33 in mice was suggested to mediate T reg cell expansion and protection by IVIG [19, 20, 27].…”

CCR2 Plays a Protective Role in Rocio Virus–Induced Encephalitis by Promoting Macrophage Infiltration Into the Brain

“…Leukocytes in the brain were isolated as previously described [14,24]. Leukocyte purification and quantification of cytokines and chemokines are briefly described in the Supplementary Methods.…”

“…Previously, it was reported that levels of multiple leukocytes, such as CD8 + T lymphocytes, macrophages, neutrophils, and CD45R + B lymphocytes, were elevated in response to ROCV infection in the CNS of BALB/c mice [13,14]. However, no leukocyte population was assessed in blood specimens in an animal model.…”

“…Despite its potential for further geographical spread, little is known about ROCV pathogenesis. In a mouse model of ROCV infection, a high virus titer was detected in the brain, and an elevated number of inflammatory macrophages was found in the central nervous system (CNS) [13,14], implying a role for macrophages during infection. However, further details on the role of these cells in the pathogenesis of ROCV have not been reported.…”

“…The CNS contains resident innate immune sentinels such as microglia that are among the first responders to infection, but peripheral leukocytes, including monocytes, and T cells, are nevertheless recruited to aid in local inflammatory responses. These cells are reported to play a role in neurotropic viral infections, including those due to WNV, coronavirus (mouse hepatitis virus), and herpes simplex virus type 1 [13][14][15][16][17]. In addition, migration of monocytes to the brain is heavily dependent on the interaction between CCL2 and its receptor, CCR2 [18][19][20].…”