TNFα Regulates SIRT1 Cleavage during Ocular Autoimmune Disease

Elevated tumor necrosis factor (TNF) alpha levels are associated with chronic autoimmune diseases in which effects of TNF alpha on immune cells are multiple and complex. Analysis of uveitis in mice exhibiting severe autoimmune inflammation, resulting in a destructive subtotal loss of photoreceptors, revealed the presence of high plasma levels of TNF alpha and a significant population of CD4(+)TNF alpha(+) cells in the periphery and the eye at peak disease (TNF alpha(hi)). We have shown previously by pharmacological activation that the deacetylase Sirtuin 1 (SIRT1) has an anti-inflammatory role in a less severe, TNF alpha(lo) model of uveitis. We now show that SIRT1 activation fails to clinically suppress severe TNF alpha(hi) disease, whereas glucocorticoid treatment is successful. TNF alpha has been reported to mediate cleavage and inactivation of SIRT1 during inflammation, and at peak disease we observed both full-length and cleaved SIRT1 in draining lymph node cells. In vivo systemic TNF alpha blockade suppressed severe ocular disease and restricted SIRT1 cleavage in the periphery, maintaining full-length active SIRT1 protein. When combining a suboptimal TNF alpha blockade with SIRT1 activation, a synergistic suppression of severe disease compared with TNF alpha blockade alone occurred. Our data suggest a new role for TNF alpha in exacerbating the severity of autoimmune disease by regulating SIRT1 cleavage in draining lymph node effector cells. SIRT1 activation may be effective as an adjunctive treatment for inflammatory conditions not fully controlled by TNF alpha inhibitors.