Summary auto-generated
This study examined cytokine production in mouse trigeminal ganglia and dorsal root entry zones following HSV-1 corneal infection using immunohistochemistry. Mice were infected with HSV-1 strain McKrae, and tissues were analyzed on days 3, 5, 7, 10, 20, and 30 post-infection. Early infection (day 3) showed TNF-α and IL-6 production by infiltrating cells surrounding virus-infected neurons, with low IFN-γ. As viral antigens cleared, TNF-α expression dramatically increased from satellite cells and Schwann cells, remaining elevated even 30 days after infection at three times normal levels. IL-2 and IL-4 appeared only after viral clearance. In the central nervous system region (dorsal root entry zone), TNF-α was the predominant early cytokine and persisted with IL-6 in astrocytes during latency. IL-10 was not detected. The authors conclude that TNF-α and IL-6, produced by infiltrating immune cells and resident glial cells, likely play crucial roles in viral clearance and neuronal homeostasis. The persistent immune response during latency may relate to continued low-level viral antigen presentation or tissue repair mechanisms rather than frequent viral reactivation.
Key findings
- TNF-α is the predominant cytokine throughout acute and latent HSV-1 infection in the trigeminal ganglion, produced by satellite cells, Schwann cells, and infiltrating immune cells, remaining elevated for at least 30 days post-infection.
- Early infection features TNF-α and IL-6 production from infiltrating cells around virus-infected neurons, while IL-2 and IL-4 appear only after viral antigen clearance.
- In the central nervous system (dorsal root entry zone), TNF-α is the sole early cytokine detected during viral clearance, later joined by IL-6 in astrocytes during latency.
- IL-10 was not detected at any timepoint, consistent with persistent TNF-α and MHC class II expression, suggesting lack of immune downregulation.
- Glial cells (satellite cells, Schwann cells, and astrocytes) are potent cytokine producers, suggesting roles for TNF-α and IL-6 in both antiviral immunity and neuronal protection/repair mechanisms.
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Abstract
Immunocytochemistry on serial paraffin sections was used to monitor the production dynamics of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF-alpha) and viral antigens in the trigeminal ganglion (TG) and the central side of the dorsal root entry zone (DRE) of mice, following infection of the cornea with herpes simplex virus type 1. In normal TG, scattered satellite cells were TNF-alpha+ and in the DRE, TNF-alpha+ and/or low numbers of IL-6+ cells were detected. On day 3 after infection, foci of TG neurons with viral antigens were surrounded by large numbers of TNF-alpha+ and/or IL-6+ cells and low numbers of IFN- gamma+ cells. IL-2+ and/or IL-4+ cells appeared later, when viral antigens had almost cleared. In the TG, the most striking changes occurred with TNF-alpha, with respect to its source (satellite cells, Schwann cells and infiltrating cells) and the extent and long duration of its production. TNF-alpha was the predominant cytokine throughout acute and latent infection and even by day 30, numbers of satellite cells expressing this cytokine were three times higher than those in normal ganglia. Moreover, in the DRE, TNF-alpha was the only cytokine detected during virus clearance and again, its production continued, along with that of IL-6, on days 20 to 30, in both infiltrating cells and astrocytes. Thus, cytokines, particularly TNF-alpha and perhaps IL- 6, from infiltrating cells and resident glial cells may have a role both in virus clearance and in normal homeostatic mechanisms in the nervous system such as repair and protection of neurons from damage.