Human host defense peptide LL-37 facilitates double-stranded RNA pro-inflammatory signaling through up-regulation of TLR3 expression in vascular smooth muscle cells.
Dahl. Sara S; Cerps. Samuel S; Rippe. Catarina C; Swärd. Karl K; Uller. Lena L; Svensson. Daniel D; Nilsson. Bengt-Olof BO
Key Findings
- LL‑37 is rapidly internalized by human vascular smooth muscle cells, indicating it can act inside cells.
- Co‑treatment with LL‑37 and synthetic dsRNA (poly I:C) dramatically boosts the production of inflammatory cytokines IL‑6 and MCP‑1 compared to either agent alone.
- The enhanced inflammatory response depends on up‑regulation of the dsRNA receptor TLR3; knocking down TLR3 eliminates the LL‑37‑mediated boost.
Practical Outcomes
- For biohackers, this suggests that increasing LL‑37 levels could amplify inflammatory reactions, especially during viral‑like dsRNA exposure, which may be undesirable for longevity or health. It does not provide a clear protocol for benefit, but serves as a caution that LL‑37 supplementation might raise inflammation risk in certain contexts.
Summary
The study shows that the human peptide LL‑37 can enter vascular smooth muscle cells and makes them react more strongly to double‑stranded RNA (a viral‑like signal) by increasing inflammation‑related proteins. This happens because LL‑37 raises the amount of the dsRNA sensor TLR3, and the effect disappears when TLR3 is blocked.
Abstract
The importance of human host defense peptide LL-37 in vascular innate immunity is not understood. Here, we assess the impact of LL-37 on double-stranded RNA (dsRNA) signaling in human vascular smooth muscle cells. Cellular import of LL-37 and synthetic dsRNA (poly I:C) were investigated by immunocytochemistry and fluorescence imaging. Transcript and protein expression were determined by qPCR, ELISA and Western blot. Knockdown of TLR3 was performed by siRNA. LL-37 was rapidly internalized, suggesting that it has intracellular actions. Co-stimulation with poly I:C and LL-37 enhanced pro-inflammatory IL-6 and MCP-1 transcripts several fold compared to treatment with poly I:C or LL-37 alone. Poly I:C increased IL-6 and MCP-1 protein production, and this effect was potentiated by LL-37. LL-37-induced stimulation of poly I:C signaling was not associated with enhanced import of poly I:C. Treatment with poly I:C and LL-37 in combination increased expression of dsRNA receptor TLR3 compared to stimulation with poly I:C or LL-37 alone. In TLR3 knockdown cells, treatment with poly I:C and LL-37 in combination had no effect on IL-6 and MCP-1 expression, showing loss of function. LL-37 potentiates dsRNA-induced cytokine production through up-regulation of TLR3 expression representing a novel pro-inflammatory mechanism.
Study Information
pubmed
2020
2020-03-27T00:00:00.000Z
10.1007/s00011-020-01340-2
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