RNA released from necrotic keratinocytes upregulates intercellular adhesion molecule-1 expression in melanocytes

Abstract

Intercellular adhesion molecule-1 (ICAM-1) expression has been detected in melanocytes around active vitiligo patches as well as in surgically transplanted melanocytes. However, it is unclear whether and how skin injury induces the inappropriate expression of ICAM-1 and other proinflammatory genes in melanocytes. We previously reported that human melanocytes expressed TLR3. We hypothesized that the TLR3 expressed in melanocytes may recognize skin injury by binding to the endogenous ligands secreted by the damaged keratinocytes. Here we showed that RNA released from necrotic keratinocytes induced the upregulation of ICAM-1 protein and mRNA, as shown by FACS and real-time RT-PCR. Use of NF-κB inhibitor prevents upregulation of ICAM-1 in melanocytes indicating a direct role of NF-κB in necrotic keratinocyte-mediated upregulation of ICAM-1. Using a shRNA-expressing lentivirus, we demonstrated that in human melanocytes, TLR3 seems to be necessary for the upregulation of ICAM-1. Using oligonucleotide microarray, we demonstrated a dramatic increase in proinflammatory cytokine and chemokine transcripts (CXCL10, CXCL11, TNFSF10, CCL5, CCL4, CCL2, IFNB1, CCL20, IL-8, and CCL11). These observations suggested that RNA released from necrotic keratinocytes might act as an endogenous TLR3 ligand for the stimulation of ICAM-1 and other proinflammatory gene expression in human melanocytes, which might be involved in the pathogenesis of vitiligo following skin physical trauma.

Cardiac RNA Induces Inflammatory Responses in Cardiomyocytes and Immune Cells via Toll-like Receptor 7 Signaling

“…We and others have demonstrated that RNase pretreatment decreases immune response induced by necrotic cells in various immune and parenchymal cells (14,25,(35)(36)(37)(38)(39). These studies conclude that endogenous exRNAs, released from or associated with injured cells, are capable of mediating inflammatory response and may contribute to tissue damage in various animal disease models.…”

Epidermal keratinocytes sense dsRNA via the NLRP3 inflammasome, mediating interleukin (IL)‐1β and IL‐18 release

“…Self-dsRNA produced from damaged keratinocytes due to UVB irradiation, mechanical trauma, wounding or other skin injury, which can be detected by TLR3 in keratinocytes and melanocytes, [24][25][26] is another potential source of cytosolic dsRNA. Type I IFNs can promote inflammasome activation and increase the secretion of IL-1β and IL-18 by upregulating PKR expression in keratinocytes.…”

“…Viral molecules can be released to the extracellular environment after damage of virus-infected cells and are present in infected cells, in which viral replication in the cytosol may supply abundant dsRNA to the cytosolic sensors. Self-dsRNA produced from damaged keratinocytes due to UVB irradiation, mechanical trauma, wounding or other skin injury, which can be detected by TLR3 in keratinocytes and melanocytes, [24][25][26] is another potential source of cytosolic dsRNA. Therefore, skin viral infection and other keratinocyte injuries are potential sources of intra-cellular and extracellular dsRNA for epidermal cells.…”

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

“…The damage‐associated molecular patterns (DAMPs) such as DNA or RNA derived from necrotic cells could activate keratinocytes . We previously reported that double‐stranded RNA (dsRNA) released from necrotic keratinocytes stimulated the upregulation of ICAM‐1 and proinflammatory cytokines in human melanocytes . Recently, it has been shown that dsRNA released by tissue damage drives skin inflammation and regeneration through TLR3 .…”

“…upregulation of ICAM-1 and proinflammatory cytokines in human melanocytes. [10] Recently, it has been shown that dsRNA released by tissue damage drives skin inflammation and regeneration through TLR3. [11] These observations have raised the possibility that the activation of dsRNA-TLR3 signalling might be involved in the induction of proinflammatory responses after skin injury.…”