Autocrine TNF‐α and IL‐1β prime 6‐sulfo LacNAc⁺ dendritic cells for high‐level production of IL‐23

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

“…Therefore, the great success of therapeutic IL‐23 inhibition in psoriasis can be attributed to its direct effects on T cells, such as their polarization into pathogenic Th17 cells, but not its involvement in the modulation of innate cytokine networks in slan‐DC. The top member of the cytokine hierarchy is TNF‐α, as its expression levels could not be modulated by any other cytokine, while autocrine TNF‐α itself displayed a feed‐forward amplification effect on all downstream slan‐DC cytokines . Interestingly, autocrine IL‐6, although identified as an early slan‐DC cytokine, did not affect slan‐DC cytokines significantly nor was its expression level significantly influenced by other slan‐DC cytokines .…”

“…They now propose an additional layer of complexity with their identification of an autocrine cytokine hierarchy that primes slan‐DC for high‐level production of IL‐23 (Fig. ) …”

“…In their recent publication in this journal, Schäkel and colleagues have proposed slan‐DC as potent producers of both IL‐23 and IL‐1β and major players in the pathogenesis of psoriasis through their ability to induce hybrid Th1/Th17 cell responses . In psoriatic skin, the frequency of slan‐DC, characterized as CD11c + CD1c − CD163 − DCs, is twice as high as compared to healthy skin.…”

“…In addition, a kinetic segregation of cytokine production by the antigen‐presenting cells might also influence T‐cell effector functions on the population level. In the recent publication by Kunze et al ,. the kinetic timeline of cytokine production by slan‐DC following lipopolysaccharide stimulation was also shown to follow a hierarchy of autocrine feed‐forward amplification loops.…”

“…As the last member of this kinetic hierarchy, IL‐23 production is potentially prone to qualitative modulation by its predecessors. Kunze et al . demonstrated that autocrine TNF‐α and IL‐1β production indeed modulated IL‐23 production levels since autocrine TNF‐α and IL‐1β inhibition using monoclonal antibodies strongly downregulated IL‐23 secretion.…”