As a Modulator, Multitasking Roles of SIRT1 in Respiratory Diseases

Abstract

As far the current severe coronavirus disease 2019 (COVID-19), respiratory disease is still the biggest threat to human health. In addition, infectious respiratory diseases are particularly prominent. In addition to killing and clearing the infection pathogen directly, regulating the immune responses against the pathogens is also an important therapeutic modality. Sirtuins belong to NAD+-dependent class III histone deacetylases. Among 7 types of sirtuins, silent information regulator type-1 (SIRT1) played a multitasking role in modulating a wide range of physiological processes, including oxidative stress, inflammation, cell apoptosis, autophagy, antibacterial and antiviral functions. It showed a critical effect in regulating immune responses by deacetylation modification, especially through high-mobility group box 1 (HMGB1), a core molecule regulating the immune system. SIRT1 was associated with many respiratory diseases, including COVID-19 infection, bacterial pneumonia, tuberculosis, and so on. Here, we reviewed the latest research progress regarding the effects of SIRT1 on immune system in respiratory diseases. First, the structure and catalytic characteristics of SIRT1 were introduced. Next, the roles of SIRT1, and the mechanisms underlying the immune regulatory effect through HMGB1, as well as the specific activators/inhibitors of SIRT1, were elaborated. Finally, the multitasking roles of SIRT1 in several respiratory diseases were discussed separately. Taken together, this review implied that SIRT1 could serve as a promising specific therapeutic target for the treatment of respiratory diseases.

Augmentation of NAD+ by Dunnione Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice

“… 33 Recently, it has been demonstrated that IL-22-induced proliferation and inflammation of keratinocytes is negatively regulated by SIRT1 through deacetylation of STAT3. 6 In this study, we also found increased STAT3 acetylation in psoriatic lesions. However, restoration of intracellular NAD + content by treatment with dunnione resulted in the downregulation of STAT3 acetylation through increased SIRT1 activity.…”

“… 29 Remarkably, SIRT1 physically interacts with nuclear translocated NF-κB p65 and deacetylates NF-κB p65 at residue Lys-310, inhibiting the transcriptional activity of NF-κB. 6 In this study, we also observed elevated NF-κB p65 acetylation in IMQ-treated skin lesions, which was facilitated by reduced SIRT1 activity induced by decreased intracellular NAD + levels. However, the increase in the cellular NAD + levels by NQO1 by dunnione resulted in downregulation of NF-κB p65 acetylation in the skin lesions, as well as production of inflammatory cytokines through increased SIRT1 activity.…”

“…However, both intracellular NAD + levels and SIRT1 activity in mouse skin lesions were significantly decreased by IMQ exposure, whereas dunnione treatment significantly attenuated these decreases ( Figure 6B and C ). Since activation of SIRT1 is known to induce deacetylation of the NF-κB subunit p65 and STAT3, 6 , 10 we measured acetylation of NF-κB p65 and STAT3 by Western blotting. As shown in Figure 6D , both were significantly increased in skin lesions of IMQ-treated mice, but these effects were completely attenuated by dunnione treatment.…”

“…5 Nuclear SIRT1 is an NAD + -dependent deacetylase that plays important roles in metabolism, aging, stress adaptation, hormone responses, and cell death through the deacetylation of substrates including NF-κB, p53, STAT3, and histones. 6 , 7 SIRT1 also inhibits oxidative stress and inflammation. 8 PARP is an abundant ADP-ribosyltransferase that functions as a DNA nick-sensor and contributes to DNA repair, chromatin remodeling, and genomic stability.…”

The sirtuin family in health and disease

“…Respiratory diseases are one of the biggest threats to human health. 590 Common respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis (LF), coronavirus disease 2019 (COVID-19), and other lung injures, seriously affect physical and mental health. 590 SIRTs have received considerable attention due to their important effects on respiratory diseases.…”