Suppressors of Cytokine Signaling 1 and 3 Are Upregulated in Brain Resident Cells in Response to Virus-Induced Inflammation of the Central Nervous System via at Least Two Distinctive Pathways

Abstract

Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS upregulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected central nervous system (CNS), and by employing various knockout mouse models, we sought to identify regulatory mechanisms that may underlie a virus induced upregulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual upregulation of SOCS1/3 mRNA expression peaking at day 7 postinfection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells, including astrocytes and some neurons, and for SOCS1 in particular this upregulation was almost entirely mediated by gamma interferon (IFN-␥) produced by infiltrating T cells. After infection with YF, we also found SOCS expression to be upregulated in brain resident cells with a peak on day 7 p.i. , but in this model, the upregulation was only partially dependent on IFN-␥ and T cells, indicating that at least one other mediator was involved in the upregulation of SOCS following YF infection. We conclude that virus-induced inflammation of the CNS is associated with upregulation of SOCS1/3 mRNA expression in brain resident cells and that at least two distinctive pathways can lead to this upregulation. IMPORTANCEIn the present report, we have studied the induction of SOCS1 and SOCS3 expression in the context of virus-induced CNS infection. We found that both a noncytolytic and a cytolytic virus induce marked upregulation of SOCS1 and -3 expression. Notably, the kinetics of the observed upregulation follows that of activity within proinflammatory signaling pathways and, interestingly, type II interferon (IFN), which is also a key inducer of inflammatory mediators, seems to be essential in initiating this counterinflammatory response. Another key observation is that not only cells of the immune system but also CNS resident cells are actively involved in both the pro-and the counterinflammatory immune circuits; thus, for example, astrocytes upregulate both C-X-C-motif chemokine 10 (CXCL10) and SOCS when exposed to type II IFN in vivo.

Differential responses of innate immunity triggered by different subtypes of influenza a viruses in human and avian hosts

“…The SOCS (suppressors of cytokine signaling) molecules were known to negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of signaling molecules [ 38 – 41 ]. The expression levels of SOCSs, especially SOCS1 and SOCS3, were found to be up-regulated in H3N2 and H5N1 HALo mutant infected cells (Fig.…”

Zika Virus-Induction of the Suppressor of Cytokine Signaling 1/3 Contributes to the Modulation of Viral Replication

“…Additionally, a close association between cytokine imbalance and SOCS1/3 observed in patients with a severe dengue infection suggested that the combined analysis of SOCS1/3, IL-10, and IL-6 expression levels could identify at-risk patients for severe dengue [38]. In an intracerebral infection mouse model, SOCS proteins were upregulated in brain resident cells in response to infection with yellow fever virus [39]. Moreover, Japanese encephalitis virus infection in mice led to an upregulation of SOCS1 and SOCS3 in vitro and in vivo in the mouse brain [17].…”

Activation of peroxisome proliferator‐activated receptor delta suppresses BACE1 expression by up‐regulating SOCS1 in a JAK2/STAT1‐dependent manner

“…; Steffensen et al . ). We and others have shown that anti‐inflammatory agents, such as glucocorticoid, rosiglitazone, resveratrol, and GW501516, induce SOCS1 expression in macrophages and microglial cells, leading to reductions in glutamate‐mediated neurotoxicity and Aβ‐triggered inflammation (Park et al .…”