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Epicutaneous administration of the pattern recognition receptor agonist
polyinosinic-polycytidylic acid activates the MDA5/MAVS pathway in Langerhans
cells
#MMPMID29509510
Tajpara P
; Schuster C
; Schön E
; Kienzl P
; Vierhapper M
; Mildner M
; Elbe-Bürger A
FASEB J
2018[Aug]; 32
(8
): 4132-4144
PMID29509510
show ga
Together with keratinocytes (KCs) and the dense network of Langerhans cells
(LCs), the epidermis is an ideal portal for vaccine delivery. Pattern recognition
receptor agonists, in particular polyinosinic-polycytidylic acid [p(I:C)], are
promising adjuvant candidates for therapeutic vaccination to generate protective
T-cell immunity. Here we established an ex vivo skin explant model to study the
expression and activation of double-stranded RNA (dsRNA)-sensing pattern
recognition receptors in LCs and KCs in human skin. Whereas KCs expressed all
known dsRNA sensing receptors at a constitutive and inducible level, LCs
exclusively expressed melanoma differentiation-associated protein 5 (MDA5) in
untreated skin and freshly isolated cells. Comparative assessments of downstream
signaling pathways induced by p(I:C) revealed distinct mitochondrial
antiviral-signaling protein, IFN-regulatory factor 3, and NF-?B activation in LCs
and KCs. Consequently, p(I:C) treatment of LCs significantly induced IFN-? and
IFN-? mRNA expression, while in KCs an up-regulation of IFN-? and TNF-? mRNA was
detectable. Stimulation of LCs with specific ligands revealed that not the TLR3-
but only the MDA5-specific ligand induced IFN-?2, IFN-?, and TNF-? cytokines, but
no IL-6 and -8. In KCs, both ligands induced production of high IL-6 and IL-8
levels, and low IFN-?2 and IFN-? levels, indicating that different dsRNA-sensing
receptors and/or downstream signaling pathways are activated in both cell types.
Our data suggest that MDA5 may be an attractive adjuvant target for epicutaneous
delivery of therapeutic vaccines with the goal to target LCs.-Tajpara, P.,
Schuster, C., Schön, E., Kienzl, P., Vierhapper, M., Mildner, M., Elbe-Bürger, A.
Epicutaneous administration of the pattern recognition receptor agonist
polyinosinic-polycytidylic acid activates the MDA5/MAVS pathway in Langerhans
cells.
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