Browse/search for people

Publication - Dr Philippa Lait

    Human Th17 cells produce a soluble mediator that increases podocyte motility via signalling pathways which mimic PAR-1 activation


    May, C, Welsh, G, Chesor, M, Lait, P, Schewitz-Bowers, L, Lee, R & Saleem, M, 2019, ‘Human Th17 cells produce a soluble mediator that increases podocyte motility via signalling pathways which mimic PAR-1 activation’. American Journal of Physiology - Renal Physiology, vol 317., pp. F913-F921


    The specific pathogenesis of idiopathic nephrotic syndrome (NS) is poorly understood and the role of immune mediators remains contentious. However, there is good evidence for the role of a circulating factor, and we recently postulated circulating proteases as candidate factors. Immunosuppressive therapy with glucocorticoids (GCs) and T cell inhibitors are widely used in the clinical treatment of NS. Given that T helper (CD4+) cells expressing IL-17A (so-called Th17 cells) have recently been reported to be resistant to GC treatment, and GC resistance remains a major challenge in the management of NS, we hypothesised that Th17 cells produce a circulating factor that is capable of signalling to the podocyte and inducing deleterious phenotypic changes. To test this, we generated human Th17 cells from healthy volunteers and added the supernatants from these T-cell cultures to conditionally immortalised human podocytes in vitro. This demonstrated that podocytes treated with Th17 cell culture supernatant, as well as with patient disease plasma, show significant stimulation of JNK and p38 MAPK pathways and an increase in motility which was blocked using a JNK inhibitor. We have previously shown that nephrotic plasma elicits a podocyte response via the protease receptor PAR-1. Stimulation of PAR-1 in podocytes elicited the same signalling response as Th17 cell culture supernatant treatment. Equally, protease inhibitors in the Th17 cell culture treatment blocked the signalling response. This was neither replicated by the reagents added to Th17 cell cultures nor by IL-17A. Hence, we conclude that an undefined soluble mediator produced by Th17 cells mimics the deleterious effect of PAR-1 activation in vitro. Given the association between pathogenic subsets of Th17 cells and GC resistance, these observations have potential therapeutic relevance for patients with NS.

    Full details in the University publications repository