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.
Highlights
Under homeostatic conditions the release of self-RNA from dying cells does not promote inflammation
To better understand the mechanism by which LL37 enables inflammatory responses, we performed RNA-sequencing to measure the transcriptome-wide effects of LL37 on primary human keratinocytes (NHEK) in the presence and absence of synthetic U1 RNA, an abundant non-coding RNA that is released upon tissue damage[18,21]
Having defined the transcriptional response of normal human epidermal keratinocytes (NHEKs) to non-coding RNA (ncRNA) in the presence of LL37, we synthesized a small series of peptides designed to interrogate the function of the N- and C-terminal domains, as well as determine the potential role of the α-helix by substitution of a proline to destabilize the peptide at position 20 (Fig. 1c)
Summary
Under homeostatic conditions the release of self-RNA from dying cells does not promote inflammation. In this scenario DNA or RNA serves as a damage associated molecular pattern (DAMP), and the cathelicidin peptide breaks immune tolerance to the presence of the nucleic acid, permitting recognition by intracellular recognition systems within the endosome and cytosol such as Toll-like receptor (TLR) 3, 7, 8, 9, mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes (STING)[14,15,16] Both direct and indirect evidence supports the critical role that LL37 plays in driving tissue inflammation including observations that the cellular expression pattern of LL37 in psoriasis directly overlaps with the expression of type-1 interferon[16]. These findings uncover a critical step in the host response to tissue damage and provide a therapeutic opportunity to block undesirable auto-inflammatory reactions
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