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Four and a half LIM domain protein 2 (Fhl2) is an intracellular adaptor molecule with a high protein protein interaction capacity. It acts as a modulator of several signaling molecules in the cytosol and as a cofactor of transcription in the nucleus. Recent studies suggest the role of Fhl2 in tissue repair and the anti-inflammatory response. Herein, we show that Fhl2-deficient mice develop a more severe psoriatic arthritis disease under induction of the inducible human tumor necrosis factor (hTNF) transgene than wild-type mice. The disease was accompanied by increased infiltration of activated macrophages and T regulatory cells in skin and digit joints as well as by increased expression of matrix metalloproteases and bone-specific proteases. The more severe pathogenesis of psoriatic arthritis in Fhl2 knockout mice coincided with enhanced Levels of soluble hTNF cytokine, but surprisingly not with transcription of the hTNF transgene. Studying the shedding of cell membrane bound hTNF by Adam17, a known Fhl2 interacting protein, revealed an enhanced release of TNF in the absence of Fhl2. In summary, our results show that Fhl2 anticipates the emerging inflammation and specifically the development of psoriatic arthritis by impeding the Adam17-mediated release of TNF.

We recently described an inducible human TNF transgenic mouse line (ihTNFtg) that develops psoriasis-like arthritis after doxycycline stimulation and analysed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of pro-inflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis-like phenotype. To reveal the contribution of T cells and macrophages to the development of TNF-mediated psoriasis, ihTNFtg mice were crossbred into RAG1(KO) mice lacking mature T and B cells. Surprisingly, the psoriatic phenotype in the double mutants was not reduced; rather, it was enhanced. The skin showed significantly increased inflammation and in particular, increased infiltration by macrophages. Consequently, depletion of macrophages in RAG1(KO) or wild-type mice led to decreased disease severity. On the contrary, depletion of Treg cells in wild-type mice increased both psoriasis and the number of infiltrating macrophages, while adoptive transfer of Foxp3-positive cells into RAG1(KO) or wild-type mice decreased both the development of psoriasis and macrophage infiltration. Thus, we conclude that Treg lymphocytes inhibit the pro-inflammatory activity of macrophages, which are the major immune effector cells in hTNF-mediated psoriasis. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Linked Commentary: .