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Abstract Number: 969

Caspase-8 Prevents Lung Fibrosis in a Murine SSc-like Disease Model By Preventing Macrophage Differentiation

Alexander Misharin1, Carla M. Cuda2, Luisa Morales-Nebreda3, Gokhan Mutlu1, GR Scott Budinger3 and Harris R. Perlman4, 1Northwestern University, Chicago, IL, 2Medicine / Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, 3Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 4Northwestern University Feinberg School of Medicine, Chicago, IL

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: fibrosis and scleroderma, Macrophage

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I

Session Type: Abstract Submissions (ACR)

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. Alternatively activated M2 macrophages have been demonstrated to be the key players in development of pulmonary fibrosis. 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 programmed necrotic cell death (necroptosis) by inhibiting the receptor-interacting serine/threonine kinase 1/3 (RIPK1/3). We have previously shown 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. We now examined specific mechanisms, responsible for this protection.

Methods Mice lacking caspase-8 specifically in DCs or macrophages were generated (CreCD11cCasp8flox/flox and CreLysMCasp8flox/flox) and examined using the bleomycin and adenoviral TGF-β models of lung fibrosis. Flow cytometric analysis was used to characterize macrophages and DC. Luminex-based QuantiGene assay was used to determine gene expression profiles and polarization of FACS-sorted macrophages.

Results We found that in the wild type mice, monocytes, recruited into the lung from the bone marrow after instillation of bleomycin, transition through the interstitial macrophage phase into alveolar macrophages, which are virtually indistinguishable from tissue-resident alveolar macrophages. However, unlike the tissue-resident macrophages, which do not exhibit profibrotic M2 phenotype, these bone marrow-derived alveolar macrophages were M2-polarized. Mice, deficient for caspase-8 in macrophages had similar number of interstitial macrophages to WT mice, but were lacking profibrotic M2 bone marrow-derived alveolar macrophages. Moreover, expression Pparg, Tgm2, Shpk and Mertk, which are important for mature alveolar macrophage phenotype, was decreased in Caspase-8-deficient bone marrow-derived alveolar macrophages.

Conclusion Our data identified bone marrow-derived alveolar macrophages and not interstitial macrophages or tissue-resident alveolar macrophages as key players and perspective target for pulmonary fibrosis in patients with scleroderma. Moreover, these data reveals a novel role for Caspase-8 in macrophage differentiation and polarization.


Disclosure:

A. Misharin,
None;

C. M. Cuda,
None;

L. Morales-Nebreda,
None;

G. Mutlu,
None;

G. S. Budinger,
None;

H. R. Perlman,
None.

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