Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Wang YH, Su B, Nestle FO, Zal T, Mellman I, Schroder JM, Liu YJ, Gilliet M.

Nature 449, 564-569 (2007)

Speaker: 張竣泓                          Time: 15:00~16:00, Nov. 14, 2007

Commentator: 謝奇璋 醫師                Place: Room 601

Abstract:

Plasmacytoid dendritic cells (pDCs), also known as type 1 interferon-producing cells, selectively express Toll-Like receptor (TLR)-7 and TLR-9 for sensing microbial RNA and DNA respectively. pDCs can promote the function of B cells, T cells, natural killer cells and myeloid DCs by rapidly secreting massive amount interferon during viral infection. Generally, pDCs do not response to self-DNA, but in some autoimmune condition, such as systemic lupus erythematosus (SLE), pDCs are able to recognize the autoantibody complex containing nucleic acid. In the psoriasis, a common chronic inflammatory disease of the skin, pDCs can infiltrate to psoriatic skin and releasing interferon. Nevertheless how pDCs are activated in this autoimmune disease is still unclear. Authors found that an anti-microbial peptide LL37 was highly expressed in psoriatic skin and could activatepDCs. Further results showed that LL37 associated with self-DNA released from dying cells would activate pDCs, and depletion of self-DNA by DNase treatment blocked the induction of IFNα expression. Combination of human DNA with LL37 could activate pDCs for IFNα in a DNA dose-dependent manner. Size-exclusion HPLC and atomic force microscropy analyses confirmed that LL37 could bind DNA and induce the formation of condensed and aggregated structure. Confocal-microscopy results showed that DNA coupled with LL37 was translocated into pDCs and retained in the early endosomes, where specifically induced TLR9 signaling and promoted IFNα secretion. In conclusion, this study discovered that an anti-microbial peptide LL37 released during skin damage could complex with self-DNA to trigger pDCs for the production of type 1 interferon. This might be the pathogenesis of psoriasis or other chronic inflammatory diseases.

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