Hierarchical governance of cytokine production by 6‐sulfo Lac NA c (slan) dendritic cells for the control of psoriasis pathogenesis

The skin immune system comprises a heterogeneous network of local cellular immune mediators. Their complex interplay establishes an efficient firstline barrier defense against pathogens and other environmental assaults. It also assures immune homeostasis and tolerance of the commensal microbiota. In psoriasis, a chronic inflammatory skin disease, the skin immune homeostasis is dysregulated resulting in immune cell infiltration and hyperplasia of epidermal keratinocytes. Th17 cells have been identified as major constituents of psoriasis pathogenesis and many other autoimmune diseases. For this reason, the analysis of their polarization conditions, effector functions and plasticity has culminated in intense research efforts over the past 10 years. Direct targeting of Th17 cell effector functions such as IL17 production (secukinumab) or Th17 differentiation (ustekinumab) has translated into great therapeutic success. An antigenpresenting cell that is hardwired for creating a microenvironment for optimal Th17 cell polarization and maintenance, has yet not been identified. Schäkel and colleagues have previously proposed human 6sulfo LacNAc+ (slan) dendritic cells (slanDC) as a major dermal dendritic cell population in psoriasis with optimal functions for creating a Th17 cell permissive microenvironment by IL23 and IL1β production.1 They now propose an additional layer of complexity with their identification of an autocrine cytokine hierarchy that primes slanDC for highlevel production of IL23 (Fig. 1).2 IL1β renders Th17 cells proinflammatory by simultaneous IL10 suppression and IFNγ upregulation (hybrid Th1/Th17 population).3 This makes IL1β a critical switch factor for imprinting a proversus antiinflammatory Th17 cell identity and thus a potentially interesting therapeutic target. In fact, autoinflammatory syndromes that are characterized by recurrent fever attacks, skin rashes, joint pain and other variable symptoms are mediated by systemic IL1β overproduction due to gain of function mutations in the NLRP3 inflammasome. This translates into a shift from antito proinflammatory Th17 cells, which can be reversed by systemic IL1β depletion. This has recently been demonstrated in patients suffering from the Schnitzler syndrome, who were treated with canakinumab, a monoclonal antibody neutralizing IL1β.4 While targeting IL1β might have dramatic effects on Th17 cell functionalities within settings of systemic IL1β overproduction, its role in psoriasis seems less profound as judged by limited efficacy of therapeutic IL1β blockade. IL23, instead, has recently emerged as a very potent therapeutic target for psoriasis. Similar to IL1β, its role in imprinting the pathogenicity of Th17 cells has been well established, particularly in mouse models.5 Its cellular source, however, remains ill defined. In their recent publication in this journal, Schäkel and colleagues have proposed slanDC as potent producers of both IL23 and IL1β and major players in the pathogenesis of psoriasis through their ability to induce hybrid Th1/Th17 cell responses.1,2 In psoriatic skin, the frequency of slanDC, characterized as CD11c+CD1c−CD163− DCs, is twice as high as compared to healthy skin. Upon stimulation of Commentary to: “Autocrine TNF-α and IL-1β prime 6-sulfo LacNAc+ dendritic cells for high level production of IL-23” by Kunze A., Förster U., Oehrl S., Schmitz M., Schäkel K.