Gilliet-LAB

Our research has focused on the understanding of mechanisms that initiate and maintain inflammation in the skin. Over the past 15 years, our research has contributed to the field by several important discoveries:

1. We identified a new inflammatory pathway of the skin based on the dermal infiltration by plasmacytoid dendritic cells (pDC) and their activation to produce type I IFNs (Gilliet et al. Arch Dermatol. 2004). We also found that this pathway is over-activated in psoriasis and lupus, where it drives chronic inflammation and disease initiation (Nestle et al. J Exp Med2005) (Lande et al. Science Transl Med. 2011). This pathway is also activated in injured skin, but it is self-limited, providing a well-controlled initial inflammatory stimulus that promotes the wound healing response (Gregorio et al. J Exp Med2011). More recently, we found that this inflammatory pathway is also at the heart of a side effect of anti-TNF treatment, called paradoxical psoriasis, which in contrast to psoriasis, is characterized by an exaggerated activation of skin pDC that does not lead to T cell autoimmunity (Conrad et al. Nat Comm 2018).
2. We have identified the factors that activate skin pDC and uncovered a fundamental function of cationic antimicrobial peptides in breaking innate tolerance to self-nucleic acids released by dying cells and activate skin pDC (Lande et al. Nature 2007). In fact, these peptides produced by keratinocytes were found to form complexes with extracellular self-nucleic acids, allowing transport into intracellular compartments of pDC where they efficiently activate nucleic acid-sensing Toll-like receptors (Lande et al. Nature 2007)(Ganguly et al J. Exp Med 2011)(Lande et al. Eur J Immunol2015). This mechanism activates skin pDC but also other cell types such as conventional DC, monocytes (Chamilos et al. Blood 2012), keratinocytes, and endothelial cells (Ramos et al. unpublished) via intracellular receptors including TLR7, 8, 9, STING and MAVS.
3. We discovered that one of these antimicrobial peptide called LL37 not only triggers innate immune activation but also acts as an epidermal autoantigen targeted by autoimmune T cells in psoriasis Lande et al. Nat Comm 2015),. These LL37-specific autoimmune T cells produce Th17 cytokines which, on one hand, elicit the psoriatic phenotype and, on the other hand, sustain the antimicrobial peptide expression by keratinocytes, providing a feedback loop that perpetuates skin inflammation in psoriasis.
4. In Systemic Lupus Erythematosus (SLE) we demonstrated that circulating immune complexes are also composed of nucleic acid-antimicrobial peptide complexes. These pathogenic complexes originate from neutrophils undergoing extracellular traps (NET) formation (Lande et al. Science Transl Med. 2011). NET-derived complexes excessively produced in SLE patients leading to an exaggerated type I IFN production by pDC and the activation of autoimmune B cells producing antibodies directed against antimicrobial peptides (Gestermann et al. 2018 submitted). These autoantibodies further stimulated NETosis in neutrophils, providing a feedback loop that sustains inflammation and autoimmunity. Thus we identified a unique pathogenic mechanism based on the formation of nucleic acid-peptide complexes which trigger innate immunity and elicit autoimmunity in psoriasis and lupus. This has opened a new research field, in which several investigators have described similar pathogenic mechanisms in other inflammatory diseases including autoimmune vasculitis, type I diabetes and atherosclerosis. Our group has also identified an antimicrobial role and a nucleic acid binding function in the TH17-derived cytokine IL-26 (Meller et al. Nat Immunol 2015). These findings point to a new inflammatory role of Th17 cells and a potential role in many other inflammatory diseases known to be Th17-driven.
5. By analyzing the tumor microenvironment of cancer, we identified a role of non-activated pDC in T regulatory cell-mediated immunosuppression (Conrad et al. Cancer Res 2012). Furthermore we have found that therapeutic activation of pDC to produce type I IFN in the tumor microenvironment can revert immunosuppression, as shown by therapeutic use of the TLR7 agonist imiquimod (Urosevic et al. J Natl Cancer Inst 2005). More recently, we found that induction of type I IFNs in the tumor by STING agonists can elicit even a stronger anti-tumor activity (Demaria et al. Nat Immunol 2015).
6. We have been involved in the initial discovery and characterization of thymic stromal lymphopoietin (TSLP) and identification of its role in driving dendritic cell mediated T helper 2-type CD4 and CD8 T cells (Soumelis et al. Nat Immunol 2002) (Gilliet et al. J Exp. Med. 2003). It is now well-accepted that this represents a key pathway that drives allergic responses in atopic dermatitis and asthma.