Burmester, Gerd, Durez, Patrick, Shestakova, Galina, Genovese, Mark, Schulze-Koops, Hendrik, Li, Yue, Lewitzky, Steven, Koroleva, Irina, Agarwal, Anni, Lee, David and Hueber, Wolfgang (2013) Caspase 8 modulates the polarisome to prevent lung fibrosis in a murine SSC-like disease model. Arthritis and Rheumatism, 65 (Suppl.). S1171. ISSN 00043591

Abstract

Background/Purpose: Pulmonary fibrosis has emerged as the leading cause of death in patients with Systemic Sclerosis (SSc). Currently available therapies are only marginally effective in treating this devastating complication and even patients who respond to therapy are left with significant respiratory morbidity. Caspase-8 is a cysteine-aspartic acid protease was originally identified as a key initiator of the apoptotic death receptor pathway and was later found to suppress necrotic programmed cell death (necroptosis) by inhibiting the receptor-interacting serine/threonine kinase 1/3 (RIPK1/3). We discovered a non-apoptotic role for caspase-8 in limiting the activation of macrophages and dendritic cells by toll-like receptor (TLR) agonists via a mechanism that involves RIPK. This novel function of caspase-8 is independent of its apoptotic function; unlike mice lacking Fas or overexpressing the general-baculoviral caspase inhibitor p35 in macrophages and DCs, the loss of caspase-8 does not result in changes in macrophage or DC numbers or affect their survival after bone marrow transplantation into lethally radiated mice. Methods: Mice lacking caspase 8 specifically in DCs or macrophages were generated (CreCD11cCasp8flox/flox CreLysMCasp8flox/flox) and examined using the bleomycin and adenoviral TGF-β models of lung fibrosis Flow cytometric analysis was used to characterize macrophage and DC. Luminexbased assays detected cytokine levels. Results: We show that mice deficient in caspase-8 specifically in macrophages and DCs (have markedly less lung fibrosis than their littermate controls following intratracheal treatment with either bleomycin or an adenovirus encoding an active form of TGF-β. In wild-type animals, we found that the development of fibrosis was accompanied by a polarization of interstitial macrophages into an alternatively activated or M2 phenotype while interstitial macrophages from animals lacking caspase-8 remained polarized toward an M1 phenotype. M2 polarized macrophages have been associated with the release of profibrotic mediators involved in tissue fibrosis and M2 polarized macrophages are found in the lungs of patients with pulmonary fibrosis. Conclusion: These data suggest a new paradigm for fibrosis in which caspase-8 functions as a key component of a “polarisome” regulating the polarization of macrophages toward an M1 or M2 phenotype. Inhibiting the function of this polarisome in macrophages from patients with scleroderma may prevent the development of lung fibrosis.

Item Type:	Article
Date Deposited:	25 Oct 2017 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/22186