Abstract
Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus. Plasmacytoid dendritic cells (pDCs) are cells specialized in robust IFN-I secretion by the engagement of endosomal TLRs, and predominantly express sialic acid-binding Ig-like lectin (Siglec)-H. However, how pDCs control endosomal TLR-mediated immune responses that cause autoimmunity remains unclear. Here we show a critical role of pDCs in TLR7-mediated autoimmunity using gene-modified mice with impaired expression of Siglec-H and selective ablation of pDCs. pDCs were shown to be indispensable for the induction of systemic inflammation and effector T-cell responses triggered by TLR7 ligand. pDCs aggravated psoriasiform dermatitis mediated through the hyperproliferation of keratinocytes and enhanced dermal infiltration of granulocytes and γδ T cells. Furthermore, pDCs promoted the production of anti-self NA antibodies and glomerulonephritis in lupus-like disease by activating inflammatory monocytes. On the other hand, Siglec-H regulated the TLR7-mediated activation of pDCs. Thus, our findings reveal that pDCs provide an essential link between TLR7-mediated innate and adaptive immunity for the initiation of IFN-I-associated autoimmune inflammation.
Highlights
Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus
Siglechkd plasmacytoid DCs (pDCs) displayed greater phosphorylation of Iκ B kinase (IKK)-α and the association of IKK-α with IFN regulatory factor (IRF)-7 following stimulation with IMQ than WT pDCs (Fig. 1f). These results indicate that sialic acid-binding Ig-like lectin (Siglec)-H suppresses the TLR7-mediated activation of the signaling cascades for nuclear factor κ B (NF-κ B) and IRF-7, which are reportedly critical for the production of proinflammatory cytokines and IFN-I in pDCs32
We demonstrated a critical function for pDCs in the induction of TLR7-mediated innate and adaptive immune responses that cause autoimmune inflammation
Summary
Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus. Dendritic cells (DCs) known as essential antigen (Ag)-presenting cells (APCs) of the immune system efficiently recognize pathogens through pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), secrete multiple cytokines and activate naïve T cells during primary responses[1,2,3] The latter property distinguishes them from other innate immune cell types, and establishes a key link between innate and adaptive immunity[4,5,6]. Siglechdtr/dtr KI mice exhibit >97% depletion of pDCs in lymphoid tissues within 24 hrs after initial DT treatment and tolerate repeated treatments with no harmful observation, allowing long-term depletion of pDCs (referred to as pDC-ablated mice) Using these KI mice, we have demonstrated that pDCs play a crucial role in the control of inflammation and T-cell responses triggered by microbial injection in vivo, and Siglec-H controls their function. PDCs have been proposed as a key source of aberrant IFN-I production in psoriasis and SLE, how they control innate and adaptive immune responses leading to the initiation of IFN-I-associated autoimmune diseases is poorly understood
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