Purpose: Nerve injury-induced pain is difficult to treat. In this study, we developed an alginate scaffold with human umbilical cord mesenchymal stem cell exosomes (EX-SC) to treat nerve injury-induced pain. Materials and Methods: The scaffold was prepared and characterized for its physical traits and biocompatibility. In vitro studies of PC12 and HEK293 cells were used to evaluate the neuroprotective and neurotrophic effects of exosomes. Right L5/6 spinal nerve ligation (SNL) was performed in Sprague-Dawley rats to induce mechanical allodynia and thermal hyperalgesia, evaluated by von Frey hair and radiant heat tests. The EX-SC was wrapped around ligated L5/6 spinal nerves for treatment. Western blotting and immunofluorescence staining were used to evaluate neuron/glial activation, cytokines and neurotrophic factor of affected dorsal root ganglion (DRG). Results: In cell culture assay, the exosomes induce neurite outgrowth of PC12 cells and protect PC12 and HEK293 cells against formaldehyde acid treatment. On post-ligation day 21, rats receiving EX-SC had significantly higher median (interquartile range) withdrawal threshold and latency [14.1 (13.7– 15.5) g, 14.2 (13.7– 15.3) s] than saline-SC-treated rats [2.1 (1.7– 3.0) g, 2.0 (1.8– 2.4) s, P=0.02 and 0.002]. The EX-SC also attenuated SNL-induced up-regulation of c-Fos, GFAP, Iba1, TNF-α and IL-1β, while enhancing the level of IL-10 and GDNF, in the ipsilateral L5/6 DRG. After implantation for 21 days, the EX-SC enhanced the expression of myelin basic protein and IL-10 in injured L5/6 axons. Conclusion: We demonstrate the EX-SC possesses antinociceptive, anti-inflammation and pro-neurotrophic effects in the SNL pain model. It could be a promising therapeutic alternative for nerve injury-induced pain.

Systemic lupus erythematosus (SLE) is a heterogeneous multisystem inflammatory disease with wide variability in clinical manifestations. Natural arising CD4+ regulatory T cells (Tregs) play a critical role in maintaining peripheral tolerance by suppressing inflammation and preventing autoimmune responses in SLE. Additionally, CD8+ regulatory T cells, type 1 regulatory T cells (Tr1), and B regulatory cells also have a less well-defined role in the pathogenesis of SLE. Elucidation of the roles of various Treg subsets dedicated to immune homeostasis will provide a novel therapeutic approach that governs immune tolerance for the remission of active lupus. Diminished interleukin (IL)-2 production is associated with a depleted Treg cell population, and its reversibility by IL-2 therapy provides important reasons for the treatment of lupus. This review focuses on the pathogenesis and new therapeutics of human Treg subsets and low-dose IL-2 therapy in clinical benefits with SLE.

Oncotarget | https://doi.org/10.18632/oncotarget.25305 Kuang-Den Chen, Ying-Hsien Huang, Mindy Ming-Huey Guo, Tzu-Yang Lin, Wei-Teng Weng, Hsiang-Jen Yang, Kuender D. Yang, Ho-Chang Kuo The human blood DNA methylome identifies crucial role of β-catenin in the pathogenesis of Kawasaki disease

The participation of antibody and complement in cell-mediated adherence and cytotoxicity to infected larvae (L3) of Angiostrongylus cantonensis was investigated in vitro. Of the different cell types involved in the reaction, neutrophils were seen to have a predominant role in immune serum—dependent adherence and cytotoxicity to L3. In the presence of immune serum, cytotoxicity to L3 by neutrophils from infected rats was twice that of neutrophils from normal rats. Although mononuclear cells and eosinophils from infected rats significantly increased the adherence to L3, they had little lethal effect on L3. A further study using gel filtration (Sephacryl S-200) and affinity chromatography (protein A) revealed that immunoglobulin G (IgG) alone was responsible for the complement activation in neutrophil-mediated killing of L3. Neither adherence nor cytotoxicity to L3 by neutrophils were affected when immune serum was heated to 50°C or treated with zymosan, but they were markedly decreased when immune serum was treated with Mg²⁺-ethylene glycol-bis-(β-aminoethyl ether)- N,N,N',N'-tetraacetic acid. The results of this study indicate that the neutrophil-mediated adherence and cytotoxicity to L3 of A. cantonensis are mediated through IgG-dependent classical complement pathway activation.

Background: Moderate physical activity has been shown to promote immunity. Different moderate physical activities may have different effects on immunity. This study investigated the impacts of a 12-week regular music aerobic exercise (MAE) program on leukocyte distribution, lymphocyte subsets, and lymphocyte polarization. Methods: The study used a case-control design with pretest and posttest. Forty-seven middle-age women were recruited for this study. Three participants dropped out, 22 completed the 12-week MAE program, and the other 22 participants who had heat-intolerance or limited schedule eligibility were enrolled as the control group without the MAE exercise. Results: Results showed that the MAE exercise for 12 weeks didn’t change red blood cells or total leukocytes but increased lymphocyte counts. The women in MAE group revealed significant increases (P ≤ 0.01) of CD3CD4, CD3CD8, and CD4CD25 cells, associated with Treg polarization showing enhanced FoxP3 but not T-bet, Gata-3, or RORγT expression ...

L-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4⁺ T cells. The biological activities of CD4⁺ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4⁺ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4⁺ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4⁺ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.