Sirtuin4 suppresses the anti‐neuroinflammatory activity of infiltrating regulatory T cells in the traumatically injured spinal cord

Abstract

Summary The neuroinflammation following traumatic spinal cord injury (SCI) is a critical process that impacts both the injury and the recovery of spinal cord parenchyma. Infiltrating regulatory T (Treg) cells are potent anti‐inflammatory cells that restrain post‐SCI neuroinflammation. To understand the molecular mechanisms underlying the activity of infiltrating Treg cells, we used a mouse spinal cord compression injury model to analyze the role of Sirtuins (SIRTs) in the modulation of infiltrating Treg cell functions. We found that the expressions of SIRT4 and SIRT6 were up‐regulated in infiltrating Treg cells. Using lentivirus‐mediated gene expression or RNA interference, we revealed that SIRT4 substantially inhibited the expression of Foxp3, interleukin‐10, and transforming growth factor‐β in Treg cells, whereas SIRT6 had little effect on Treg cells. Consistently, SIRT4 overexpression weakened the suppressive effect of Treg cells on lipopolysaccharide‐stimulated spinal cord CD11b+ myeloid cells. Knock‐down of SIRT4 enhanced the anti‐inflammatory activity of infiltrating Treg cells in the parenchyma of injured spinal cords. Additionally, SIRT4 overexpression blocked in vitro Treg cell generation from conventional T cells. Furthermore, SIRT4 down‐regulated 5′ AMP‐activated protein kinase (AMPK) signaling in Treg cells, whereas the AMPK agonist AICAR restored the expression of Foxp3 and interleukin‐10 in SIRT4‐overexpressing Treg cells. In conclusion, our research unveils a new mechanism by which the post‐SCI neuroinflammation is regulated.

Metabolic signaling in T cells

“…Similar to SIRT1, SIRT4 regulates FoxP3 stability and Treg cell function. 160 More generally, SIRT1 regulate the balance of Th17-Treg differentiation. T cell-specific deletion of SIRT1 and SIRT1-specific inhibitors suppress the Th17 program and are protective in mouse models of experimental autoimmune encephalomyelitis (EAE).…”

Irisin Protects Against Motor Dysfunction of Rats with Spinal Cord Injury via Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase-Nuclear Factor Kappa-B Pathway

“…for 28 consecutive days (each day at 8 am). Doses of irisin were selected based on previous studies ( Zhao et al, 2018 ; Aydogdu et al, 2019 ). Irisin solutions were prepared via dissolving irisin powder (a recombinant protein of animal origin that can be used in human, rat, mouse and canine experiments, catalogue number: 067-29A, Phoenix Pharmaceuticals Inc., Burlingame, USA) in normal saline.…”

How T'reg‐ulate healing of the injured spinal cord?

“…In this month’s issue, Lin and colleagues describe how both SIRT6 and SIRT4 are expressed in the Treg population that infiltrates the spinal cord after a compression injury. They show that SIRT4 functions to suppress the anti‐neuroinflammatory activity of these infiltrating Treg cells . Thus, when SIRT4 was genetically suppressed using short hairpin RNAs in vitro and in vivo , the transcription of anti‐inflammatory factors, FoxP3, interleukin‐10, and transforming growth factor beta all increased.…”

“…They show that SIRT4 functions to suppress the anti-neuroinflammatory activity of these infiltrating Treg cells. 7 Thus, when SIRT4 was genetically suppressed using short hairpin RNAs in vitro and in vivo, the transcription of anti-inflammatory factors, FoxP3, interleukin-10, and transforming growth factor beta all increased. The anti-inflammatory effects of knocking down SIRT4 were not only observed in Treg interactions with spinal cord CD11b + myeloid cells in vitro, but also in Tregs in the spinal cord parenchyma.…”