Keratinocyte-intrinsic BCL10/MALT1 activity initiates and amplifies psoriasiform skin inflammation
Zsuzsanna Kurgyis, Larsen Vornholz, Konstanze Pechloff, Lajos V. Kemény, Tim Wartewig, Andreas Muschaweckh, Abhinav Joshi, Katja Kranen, Lara Hartjes, Sigrid Möckel, Katja Steiger, Erik Hameister, Thomas Volz, Mark Mellett, Lars E. French, Tilo Biedermann, Thomas Korn, Jürgen Ruland
Abstract
gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1β, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.