Immune system’s toll-like receptor 8 may be SSc therapeutic target

Contrary to earlier finding, TLR8 not present in plasmacytoid dendritic cells
by Margarida Maia, PhD | October 1, 2024

​Activating TLR8, a viral defense mechanism involved in tissue fibrosis (scarring), primes monocytes isolated from the blood of people with systemic sclerosis (SSc) to produce excess amounts of a a molecule called IL-10 that can contribute to the abnormal growth of fibrotic tissue.

The finding opens up possibilities for new therapeutic targets, according to researchers.
“IL-10 could contribute to the fibrotic skin changes that are characteristic of systemic sclerosis,” Theresa Graalmann, PhD, senior study author at the Twincore Center for Experimental and Clinical Infection Research in Hannover, Germany, said in a Twincore press release. “Developing a better molecular understanding of the inflammatory reactions during such a disease is the first step on the road to new and better therapies for the affected patients. However, we cannot yet draw any direct conclusions for treatment because the number of patients is so small.”

The study, “Toll-Like Receptor 8 is Expressed in Monocytes in Contrast to Plasmacytoid Dendritic Cells and Mediates Aberrant Interleukin-10 Responses in Patients With Systemic Sclerosis,” was published as a brief report in Arthritis & Rheumatology.

In SSc, or scleroderma, the immune system mistakenly attacks tissues, leading to fibrosis. When scar tissue accumulates, it causes the skin to become thick and stiff, but can also affect internal organs.
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As a part of the immune system, so-called toll-like receptors (TLRs) help to recognize and fight against infections. In SSc, however, TLRs like TLR8 appear to become overly activated, causing a harmful immune response instead of being protective.

TLR8’s contribution to SSc
Graalmann’s researchers investigated how TLR8 may contribute to SSc by looking at its levels in immune cells, with a focus on dendritic cells and monocytes. Dendritic cells help start an immune response, whereas monocytes travel in the blood to tissues, where they call on other immune cells to mount a response.

The researchers isolated immune cells from the blood and skin of 16 people with SSc, 10 with primary Sjögren’s disease, another autoimmune disease, and 13 healthy people who served as controls. They then used a laser-based technique to check the immune cells for TLR8 and other molecules.

“We examined these cells using flow cytometry,” said Christine Ehlers, a PhD student at Twincore and one of the study’s researchers. “This enables us to measure the concentration of receptors and immune messengers, so-called cytokines, in the cells.”

In all three groups, TLR8 was present in monocytes and dendritic cells. Contrary to earlier findings, TLR8 wasn’t present in plasmacytoid dendritic cells, a rare type of immune cell that releases large amounts of interferon in response to infections.

When TLR8 was activated to set off its signaling pathway, monocytes from people with SSc responded with an increased production of IL-10 compared with healthy people. This response wasn’t seen in plasmacytoid dendritic cells, which didn’t produce interferon with TLR8 activation. IL-10 is an anti-inflammatory cytokine that may contribute to the abnormal growth of fibrotic tissue.

“The monocytes from the scleroderma samples showed increased production of IL-10 after activation of TLR8. We did not observe this in our control group with Sjögren’s syndrome,” Ehlers said.
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“In contrast to the previously published hypothesis of aberrant TLR8 expression [presence] in [plasmacytoid dendritic cells], we suggest that in patients with SSc, TLR8 signaling in monocytes results in increased IL-10 levels and thus contributes to SSc,” the researchers wrote.