Sirtuin-1 in immunotherapy: A Janus-headed target

Abstract

Sirtuin‐1 (Sirt1), a member of the NAD‐dependent sirtuin family of histone/protein deacetylases (HDAC), is an important target for immunotherapy due to its role in deacetylating the transcription factors Foxp3 and thymic retinoid acid receptor related orphan receptor gamma (RORγt). Sirt1 inhibition can increase Foxp3 acetylation and promote the production and functions of Foxp3+ T‐regulatory (Treg) cells, whereas the acetylation of RORγt decreases its transcriptional activity DNA binding and decreases the differentiation of proinflammatory Th17 cells. Pharmacologic inhibitors of Sirt1 increase allograft survival and decrease autoimmune colitis and experimental allergic encephalomyelitis. However, in contrast to its role in T cells, Sirt1 has anti‐inflammatory effects in myeloid cells, and, context dependent, in Th17 cells. Here, inhibition of Sirt1 can have proinflammatory effects. In addition to effects arising from the central role of Sirt1 in cellular metabolism and NAD‐dependent reactions, such proinflammatory effects further complicate the potential of Sirt1 for therapeutic immunosuppression. This review aims to reconcile the opposing literature on pro‐ and anti‐inflammatory effects of Sirt1, provides an overview of the role of Sir1 in the immune system, and discusses the pros and cons associated with inhibiting Sirt1 for control of inflammation and immune responses.

Per2 Upregulation in Circulating Hematopoietic Progenitor Cells During Chronic HIV Infection

“…An important role of Sirtuin family has been described in the regulation of inflammatory response (Hwang et al, 2013 ; Mendes et al, 2017 ; Chadha et al, 2019 ). Sirt1 has been shown to suppress NF-κb activity, the regulator of cellular inflammatory response and increase antioxidant gene expression that suppressed inflammation (Mendes et al, 2017 ).…”

“…Moreover, several studies reported that Per2 is regulated at multiple layers by Sirtuin 1, a protein deacetylase that negatively regulates Per2 expression in aging process (Asher et al, 2008 ; Chang and Guarente, 2013 ; Wang R. H. et al, 2016 ). Moreover, Sirtuin 1 is considered a multitask molecule as it may act on co-activators, transcription factors, and signaling molecules (p53), forkhead box O1 (FOXO, and RelA/p65) (Rajendrasozhan et al, 2009 ) with anti-apoptotic, anti-aging, and anti-inflammatory properties (Rahman et al, 2012 ; Hwang et al, 2013 ; Mendes et al, 2017 ; Chadha et al, 2019 ). Interestingly, Kwon et al ( 2008 ) reported that HIV transactivator Tat inhibits the Sirt1 deacetylase, resulting in increased acetylation of NF-kB and subsequently in T cell hyperactivation.…”

The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

“…On the contrary, deacetylation of RORγt by Sirtuin-1 enhanced its transcriptional activity and favored the differentiation of Th17 cells. SIRT1 inhibitors suppressed Th17 differentiation and were protective in a mouse model of multiple sclerosis and IBD [103][104][105].…”

Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells

“…It should also be considered, that inhibitors of sirtuin enzymes can induce different changes in distinct cell types of anticancer immunity. In myeloid cells, SIRT1 inhibition leads to increased transcription of proinflammatory cytokines, but on the other hand, targeting SIRT1 results in net immunosuppressive effect in case of T cells (93).…”