Interferon gamma induces protective non‐canonical signaling pathways in primary neurons

Abstract

The signal transduction molecule, Stat1, is critical for the expression of type I and II interferon (IFN)-responsive genes in most cells; however, we previously showed that primary hippocampal mouse neurons express low basal Stat1, with delayed and attenuated expression of IFN-responsive genes. Moreover, IFNγ-dependent resolution of a neurotropic viral challenge in permissive mice is Stat1-independent. Here, we show that exogenous INFγ has no deleterious impact on neuronal viability, and staurosporine-induced apoptosis in neurons is significantly blunted by the addition of INFγ, suggesting that INFγ confers a pro-survival signal in neurons. To identify the pathways induced by INFγ in neurons, the activation of alternative signal transducers associated with INFγ signaling was assessed. Rapid and pronounced activation of extracellular signal regulated kinase (Erk1/2) was observed in neurons, compared to a modest response in fibroblasts. Moreover, the absence of Stat1 in primary fibroblasts led to enhanced Erk activation following IFNγ addition, implying that the cell-specific availability of signal transducers can diversify the cellular response following IFN engagement.

Current prospects of type II interferon γ signaling and autoimmunity

“…1B), IFN␥ can activate STAT3, in a JAK-STAT-dependent process that results in activation of GAS-regulated genes (15,16). Moreover, the absence of Stat1 in primary fibroblasts or neurons led to enhanced ERK activation following IFN␥ addition, implying that the cell-specific availability of signal transducers can diversify the cellular response following IFN engagement (17). STAT-independent IFN␥ signaling can occur via activation of other MAPKs, such as PyK2, ERK1/2, and JNK (18,19); the adaptor proteins CrkL and small G protein Rap1 (20); and the Src homology 2 domaincontaining protein-tyrosine phosphatases SHP-1 and SHP-2 (18,21).…”

Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNα/β Defense Pathways

“…2, A and B). Though IFNγ-induced neuroprotective signaling through Erk1/2 has been described (31), Erk1/2 phosphorylation was increased in TG from all experimental groups pursuant to HSV-1 infection irrespective of measured IFN ligand availability (Fig. 2 C).…”

“…Ancillary IFN signaling also propagates physiological changes through STAT1-independent mediators such as the mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and protein kinase B (PKB/AKT) pathways to elicit antiviral defenses (28–31). Though these signaling pathways are also active in healthy nerve ganglia, modulation of such responses is likely important for control of HSV-1 in the peripheral nervous system.…”

“…Though these signaling pathways are also active in healthy nerve ganglia, modulation of such responses is likely important for control of HSV-1 in the peripheral nervous system. For example, IFNα/β/γ-dependent STAT1 phosphorylation is reportedly subdued in neurons relative to mitotically-active cells as a measure of protection against cytotoxicity (31, 32). …”

“…Downstream signaling pathways mediated by IFNα/β signaling and STING are highly regulated (66). Accumulating evidence suggests that neurons exhibit a predilection for alternative IFN signaling cascades relative to mitotically active cells—a strategy of protection against cytotoxicity (31, 32); this differs from the orthodox supposition that STAT1-dependent ISG responses arbitrate antiviral defenses ubiquitously.…”