Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors

Abstract

Under homeostatic conditions the release of self-RNA from dying cells does not promote inflammation. However, following injury or inflammatory skin diseases such as psoriasis and rosacea, expression of the cathelicidin antimicrobial peptide LL37 breaks tolerance to self-nucleic acids and triggers inflammation. Here we report that LL37 enables keratinocytes and macrophages to recognize self-non-coding U1 RNA by facilitating binding to cell surface scavenger receptors that enable recognition by nucleic acid pattern recognition receptors within the cell. The interaction of LL37 with scavenger receptors was confirmed in human psoriatic skin, and the ability of LL37 to stimulate expression of interleukin-6 and interferon-β1 was dependent on a 3-way binding interaction with scavenger receptors and subsequent clathrin-mediated endocytosis. These results demonstrate that the inflammatory activity of LL37 is mediated by a cell-surface-dependent interaction and provides important new insight into mechanisms that drive auto-inflammatory responses in the skin.

Expression and Function of Host Defense Peptides at Inflammation Sites

“…This enhances production of large amounts of type I IFN, leading to the functional activation of myeloid dendritic cells (mDCs), monocytes, NK cells, keratinocytes, as well as Th1/Th17 differentiation, which further increase the pro-inflammatory, e.g., IFN-γ, IL-22, and IL-17, cytokine expression [120,121]. In line with this, a novel mechanism of nucleic acid recognition by LL-37 utilizing cell surface RNA scavenger receptors (SRs) has been described [122], which results is enhanced clathrin-dependent endocytosis, facilitating the overproduction of inflammatory cytokines and chemokines. Recently also RNase7 was found to utilize plasmacytoid dendritic cell (pDC) TLR-9 signaling mode of IFN-α activation even more strongly than LL-37, emphasizing its crucial role in autoimmune inflammatory skin diseases [123].…”

A novel technique to diagnose non‐melanoma skin cancer by thermal conductivity measurements: Correlations with cancer stromal factors

“…On the other hand, LL37 promotes the viability, migration, and invasion of malignant melanoma cells through Y‐box binding protein 1 (YB‐1)‐dependent pathways . As a previous report suggested, LL37 binds surface scavenger receptors that enable macrophages to recognise self‐non‐self‐coding U1 RNA . Since the tumor microenvironments of SCC and EMPD possess substantial numbers of CD163+ M2‐polarised TAMs, especially in invasive phenotypes, increased levels of LL37 in invasive phenotypes might stimulate TAMs in SCC and EMPD via scavenger receptors (CD163).…”

“…LL37 is an amphipathic cationic peptide that can induce various immunomodulatory functions, including induction of inflammation and anti‐tumor immune responses . On the other hand, LL37 promotes the viability, migration, and invasion of malignant melanoma cells through Y‐box binding protein 1 (YB‐1)‐dependent pathways .…”

“Shedding Light” on How Ultraviolet Radiation Triggers Rosacea

“…Cell extracts from a UVR-damaged keratinocyte cell line (normal human epidermal keratinocytes [NHEK]) were then shown to upregulate these adhesion molecules in an endothelial cell line (human dermal microvascular endothelial cells [HDMEC]). Since the Gallo group previously discovered that LL-37 bound to self-RNAeactivated keratinocytes and innate immune cells (macrophages) (Takahashi et al, 2018), the authors then used RNAse III to demonstrate that adhesion molecule upregulation required RNA. Finally, the authors determined that LL-37 and a model self-RNA molecule (synthetic snoU1 double-stranded RNA [dsRNA]) could reproduce this phenomenon.…”

“…For instance, can this pathway be initiated by UVR damage to any keratinocyte or must damage occur in a keratinocyte near a dermal capillary? Since cathelicidin is normally concentrated in the superficial epidermis (Braff et al, 2005), the diffusion of superficially released LL-37:dsRNA might be impeded by LL-37's intrinsic affinity for cell membranes (Vandamme et al, 2012) or by scavenger receptors on keratinocytes (Takahashi et al, 2018). This paper demonstrated that LL-37 is present throughout rosacea epidermis, so there may be sufficient LL-37 to allow (1) LL-37:dsRNA to traverse the entire epidermis or (2) be available to bind dsRNA released from keratinocytes closer to the dermal-epidermal junction.…”