Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

Inhibiting scar formation in vitro and in vivo by adenovirus-mediated mutant Smad4: a preliminary report.

The best characterized signalling pathway employed by transforming growth factor-beta (TGF-ß) is the Smad pathway. We focused on Smad4, because it is essential for the activation of Smad-dependent target genes. We aimed to explore the possibility of inhibiting scar formation after wounding by blocking TGF-ß signalling by means of a gene therapy approach using adenovirus-mediated expression of mutant Smad4. The coding sequence of the dominant-negative mutant Smad4ΔM4, which has a deletion in the linker region of Δ275-322, was introduced by homologous recombination into an adenovirus vector to generate the recombinant vector Ad-ΔM4, which encoded Smad4ΔM4. Mouse fibroblast NIH 3T3 cells were transfected with Ad-ΔM4 and cell proliferation, collagen protein production, and the expression of collagen type I and type III mRNA were evaluated in vitro using a cell proliferation test, western blot analysis, and RT-PCR, respectively. Cell proliferation and the expression of collagen type I and type III mRNA and protein were all inhibited by the transfection of Ad-ΔM4. In vivo, Ad-ΔM4 was applied externally to wounds on rats, and histological examination and quantification of the scars were performed to evaluate the curative effect. The transfection of Ad-ΔM4 successfully inhibited scar formation in rat wounds. In conclusion, Ad-ΔM4 can block the TGF-ß signalling of mouse wound cells effectively. In addition, gene therapy with Ad-ΔM4 can effectively inhibit wound scarring in rats and may potentially be applied to clinical treatment of scars.

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance.

Calcineurin acts as a calcium-activated phosphatase that dephosphorylates various substrates, including members of the nuclear factor of activated T cells (NFAT) family, to trigger their nuclear translocation and transcriptional activity. However, the detailed mechanism regulating the recruitment of NFATs to calcineurin remains poorly understood. Here, we report that calcineurin A (CNA), encoded by PPP3CB or PPP3CC, is constitutively ubiquitinated on lysine 327, and this polyubiquitin chain is rapidly removed by ubiquitin carboxyl-terminal hydrolase 16 (USP16) in response to intracellular calcium stimulation. The K29-linked ubiquitination of CNA impairs NFAT recruitment and transcription of NFAT-targeted genes. USP16 deficiency prevents calcium-triggered deubiquitination of CNA in a manner consistent with defective maintenance and proliferation of peripheral T cells. T cell-specific USP16 knockout mice exhibit reduced severity of experimental autoimmune encephalitis and inflammatory bowel disease. Our data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. Notably, our results highlight a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.

Foster replantation of fingertip using neighbouring digital artery in a young child.

UNLABELLED: Reconstruction of an amputated fingertip in a young child demands special techniques for success. We report a 2.5-year-old female patient with an amputated left index fingertip with the vascular defect being too severe to perform the usual replantation. Comparing several methods, we used the neighbouring digital artery as the feeding artery to perform foster replantation. Finally, the patient was satisfied with the appearance and function of her fingers. The clinical case, techniques, results are described and discussed. We consider it a useful technique, especially for those with a rather severe vascular defect. PATIENT: A 2.5-year-old girl suffered a crush amputation of the left index fingertip. Only the flexor tendon of the amputated fingertip was connected to the proximal finger tissue and the blood supply was completely lost (Figure 1). METHODS: The distal amputated fingertip was fixed using Kirschner wire under general anaesthesia. Then, microsurgery operation was carried out immediately to replant this amputated fingertip. Both ulnar and radial digital arteries were avulsed, while the dorsal vein was intact and the digital nerve was also surviving. The integrity of blood vessels was too traumatised to connect to the proximal part. In the case of the distal part of the ulnar artery of the injured index finger, the blood supply was established by anastomosing the distal end of the amputated tip and the radial artery of the middle finger, which was the feeding artery (Figure 2). A 11/0 nylon suture was used. The dorsal vein and digital nerve were repaired by means of microsurgical anastomosis. The wound was covered with the dorsal skin of the middle finger and the palmar skin of the index finger to form a skin pedicle, and then, immobility of the two fingers was maintained to prevent avulsion. RESULT: The index tip obtained good blood supply and survived completely (Figure 3). Detachment of the index and middle finger was performed after 3 weeks, and both of the fingers showed good blood supply (Figure 4). The appearance and function of the index and middle fingers were satisfactory 3 months postoperatively.