Background We and others have reported that selective histone deacetylase 6 (HDAC6) inhibition decreases inflammation in a variety of animal models including inflammatory arthritis and lupus. In this study, we explored whether HDAC6 gene deletion could affect pristane-induced lupus.
Methods C57BL/6 (w.t.) and HDAC6-/- C57BL/6 mice were given 0.5 ml of pristine intraperitonealy (ip) at 3 months of age. Injection of pristane induces a lupus-like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b(+) Ly6C(high) inflammatory monocytes in a TLR7-dependent fashion. Two weeks after pristane administration the mice were euthanized and assessed for various parameters of inflammation. At termination of the experiment, serum, peritoneal macrophages, and splenic tissue was collected and evaluated.
Results The pristine treated animals euthanized showed diffuse alveolar hemorrhage, both w.t. and knock-outs. At sacrifice, spleens were significantly larger in the HDAC6-/- mice compared to the w.t. pristine mice, however when compared to body weights there was not a significant difference. Flow cytometry did not indicate any differences in T cell or B cell populations. Sera IL-12, IL-6, TGF-β, IL-10, and TNF-α were comparable in the w.t. and the knock-out animals treated with pristine. Peritoneal recruitment of CD11b(+) Ly6C(high) inflammatory monocytes in HDAC6-/- mice was significantly increased compared to the w.t. mice. Evaluation of the transcripts for several IFN inducible genes revealed significantly increased IRF-7 expression in the HDAC6-/- mice however lower expression of IFN β and IRF-9.
Conclusions Taken together, our results show that in early lupus induction with pristine, HDAC6 gene deletion alters monocyte activation and differentially regulates IFN inducible genes.
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