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

Summary

Regulatory T cells (Tregs) are important for limiting inflammation‐dependent damage in neural tissue. However, Tregs have also been shown to inhibit neural repair associated with type 2 (anti‐inflammatory/wound healing) immune responses. Recently, it was demonstrated that Sirtuins, a family of proteins that contribute to the control of cellular responses to metabolic stimuli, influence the functions of Tregs. Specifically, SIRT4 was found to suppress the anti‐neuroinflammatory activity of Tregs infiltrating the spinal cord following injury; when SIRT4 expression was genetically suppressed, Tregs made more anti‐inflammatory factors, IL‐10, FoxP3, and transforming growth factor beta (TGFβ). Thus, understanding how the SIRT4‐Treg pathway can be manipulated could provide useful avenues to control both pathogenic and neuroprotective immune responses.

After the spinal cord is traumatically injured, inflammatory responses are induced. As in other tissues, these responses are an intrinsic component of the healing process, but they can also lead to tissue damage that is more severe than would be expected from the original injury.1 In the spinal cord, this secondary damage can be significant; more so in animals lacking CD4 T cells. The adaptive immune response, therefore, can function to prevent excessive neuroinflammation and to promote healing and repair. The functions of FoxP3⁺ Tregs in these processes are potentially very important, but difficult to elucidate. Tregs have been described as protective, inhibiting damaging inflammatory responses in models of stroke.2 There is evidence they may also be protective in models of immune‐mediated neuro‐degeneration, and in humans with amyotrophic lateral sclerosis.3 However, Tregs have also been shown to inhibit repair‐ and healing‐promoting adaptive and innate type 2 responses, thus potentially worsening secondary damage after neuronal injury4 in a model of ischaemic stroke. Consequently, the molecular mechanisms involved in Treg functions in neural tissue are worthy of study.

Sirtuins are a family of seven homologous proteins, silent information regulator 1‐7 (SIRT1‐7), that function to deacetylate lysine residues on a wide variety of proteins. Members of this family, particularly SIRT1, play important roles in controlling metabolic processes, including in immune cells.5 SIRT4 contributes to controlling cellular metabolic responses; it is repressed by the mTORC1 pathway, therefore enabling glutamine metabolism and stimulating cell proliferation.6 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.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.

The mechanism through which SIRT4 appears to operate is by inhibiting 5’ AMP‐activated protein kinase (AMPK) signalling in mitochondria. SIRT4 acts as an ADP‐ribosyl transferase in mitochondria, increasing cellular ATP levels, and therefore inhibiting AMPK signalling. AMPK is normally highly expressed and active in Tregs,8 so the effect of SIRT4, in reducing AMPK function, leads to reduction in the Tregs’ suppressive capacity.

To promote repair in the spinal cord after injury, a balance must be struck between potentially damaging inflammatory responses and neuroprotective wound healing type 2 responses. One function of SIRT4 may be to contribute to this balance. SIRT4 suppresses the production of anti‐inflammatory effector cytokines by Tregs, allowing increased activation of both T cells and CD11b⁺ myeloid cells in the environment surrounding the site of injury. If appropriate type 2 innate and T cell‐mediated responses occur following injury, the expression of SIRT4 may facilitate healing. Conversely, in pathological situations, where inappropriate inflammatory responses occur in neural tissues, this SIRT4 ‐mediated effect on Tregs is likely to increase inflammation and worsen pathology. Thus, an improved understanding of the Sirtuin pathway may be critical for developing treatments for inflammation‐mediated neurodegenerative disorders, in which secondary neuroinflammation could be manipulated towards repair.