PEPITEM modulates leukocyte trafficking to reduce obesity-induced inflammation.

Dysregulation of leukocyte trafficking, lipid metabolism, and other metabolic processes are the hallmarks that underpin and drive pathology in obesity. Current clinical management targets alternations in lifestyle choices (e.g. exercise, weight loss) to limit the impact of the disease. Crucially, re-gaining control over the pathogenic cellular and molecular processes may offer an alternative, complementary strategy for obese patients. Here we investigate the impact of the immunopeptide, PEPITEM, on pancreas homeostasis and leukocyte trafficking in mice on high-fed obesogenic diet (HFD). Both prophylactic and therapeutic treatment with PEPITEM alleviated the effects of HFD on the pancreas, reducing pancreatic beta cell size. Moreover, PEPITEM treatment also limited T-cell trafficking (CD4+ T-cells and KLRG1+ CD3+ T-cells) to obese visceral, but not subcutaneous, adipose tissue. Similarly, PEPITEM treatment reduced macrophage numbers within the peritoneal cavity of mice on HFD diet at both 6 and 12 weeks. By contrast, PEPITEM therapy elevated numbers of T and B cells were observed in the secondary lymphoid tissues (e.g. spleen and inguinal lymph node) when compared to the untreated HFD controls. Collectively our data highlights the potential for PEPITEM as a novel therapy to combat the systemic low-grade inflammation experienced in obesity and minimize the impact of obesity on pancreatic homeostasis. Thus, offering an alternative strategy to reduce the risk of developing obesity-related co-morbidities, such as type 2 diabetes mellitus, in individuals at high risk and struggling to control their weight through lifestyle modifications.

Aging modulates homeostatic leukocyte trafficking to the peritoneal cavity in a sex-specific manner.

Aging is associated with exacerbated systemic inflammation (inflammaging) and the progressive loss of immune system function (immunosenescence). Leukocyte migration is necessary for effective immunity; however, dysregulated trafficking of leukocytes into tissue contributes to inflammaging and the development of age-related inflammatory diseases. Aging modulates leukocyte trafficking under inflammatory conditions; however, whether aging modulates leukocyte trafficking under homeostatic conditions remains to be elucidated. Although immune responses are evidently sexually dimorphic, limited studies have investigated the effect of sex on age-related changes to leukocyte trafficking processes. Here, we investigated age-related and sex-specific changes to the leukocyte populations within the peritoneal cavity of young (3-mo), middle-aged (18-mo) and old (21-mo) male and female wild-type mice in the steady state. We found an age-related increase in the number of leukocytes within the peritoneal cavity of female mice, predominantly B cells, which may reflect increased trafficking through this tissue with age. This was accompanied by an increased inflammatory environment within the aged cavity, including increased levels of chemoattractants, including B cell chemoattractants CXCL13 and CCL21, soluble adhesion molecules, and proinflammatory cytokines, which was more pronounced in aged female mice. Intravital microscopy techniques revealed altered vascular structure and increased vascular permeability within the peritoneal membrane of aged female mice, which may support increased leukocyte trafficking to the cavity with age. Together, these data indicate that aging affects homeostatic leukocyte trafficking processes in a sex-specific fashion.

Galectin-9 supports primary T cell transendothelial migration in a glycan and integrin dependent manner.

Adaptive immunity relies on the efficient recruitment of T cells from the blood into peripheral tissues. However, the current understanding of factor(s) coordinating these events is incomplete. Previous studies on galectin-9 (Gal-9), have proposed a functionally significant role for this lectin in mediating leukocyte adhesion and transmigration. However, very little is known about its function in T cell migration. Here, we have investigated the role of the Gal-9 on the migration behaviour of both human primary CD4+ and CD8+ T cells. Our data indicate that Gal-9 supports both CD4+ and CD8+ T cell adhesion and transmigration in a glycan dependent manner, inducing L-selectin shedding and upregulation of LFA-1 and CXCR4 expression. Additionally, when immobilized, Gal-9 promoted capture and firm adhesion of T cells under flow, in a glycan and integrin-dependent manner. Using an in vivo model, dorsal air pouch, we found that Gal-9 deficient mice display impaired leukocyte trafficking, with a reduction in pro-inflammatory cytokines/chemokines generated locally. Furthermore, we also demonstrate that Gal-9 inhibits the chemotactic function of CXCL12 through direct binding. In conclusion, our study characterises, for the first time, the capture, adhesion, and migration behaviour of CD4+ and CD8+ T cells to immobilised /endothelial presented Gal-9, under static and physiological flow conditions. We also demonstrate the differential binding characteristics of Gal-9 to T cell subtypes, which could be of potential therapeutic significance, particularly in the treatment of inflammatory-based diseases, given Gal-9 ability to promote apoptosis in pathogenic T cell subsets.

Dysregulation of Leukocyte Trafficking in Type 2 Diabetes: Mechanisms and Potential Therapeutic Avenues.

Type 2 Diabetes Mellitus (T2DM) is a chronic inflammatory disorder that is characterized by chronic hyperglycemia and impaired insulin signaling which in addition to be caused by common metabolic dysregulations, have also been associated to changes in various immune cell number, function and activation phenotype. Obesity plays a central role in the development of T2DM. The inflammation originating from obese adipose tissue develops systemically and contributes to insulin resistance, beta cell dysfunction and hyperglycemia. Hyperglycemia can also contribute to chronic, low-grade inflammation resulting in compromised immune function. In this review, we explore how the trafficking of innate and adaptive immune cells under inflammatory condition is dysregulated in T2DM. We particularly highlight the obesity-related accumulation of leukocytes in the adipose tissue leading to insulin resistance and beta-cell dysfunction and resulting in hyperglycemia and consequent changes of adhesion and migratory behavior of leukocytes in different vascular beds. Thus, here we discuss how potential therapeutic targeting of leukocyte trafficking could be an efficient way to control inflammation as well as diabetes and its vascular complications.

The impact of forced swimming on expression of RANKL and OPG in a type 2 diabetes mellitus rat model.

OBJECTIVE: The importance of swimming in bone metabolism during type 2 diabetes (T2DM) is not well known. Receptor activator of nuclear factor-kB ligand (RANKL)/ osteoprotegerin (OPG) system as a critical pathway in bone remodeling may play a role in pathogenesis of T2DM. Hence, we tested this pathway and the possible beneficial effects of swim training on T2DM. MATERIALS AND METHODS: Forty male rats were assigned to groups (n = 10): control(C), diabetic (D), exercised control (E), and diabetic exercised (DE). One week after the induction of diabetes, animals were subjected to swim. At the end of training, fasting blood sugar, insulin, bone and serum OPG and RANKL levels were measured. RESULTS: Diabetes significantly increased OPG and decreased RANKL mRNAs and proteins in bone and serum and swim training could reverse these changes to control. CONCLUSION: Swim training could partially compensate T2DM associated changes of bone and serum OPG/RANKL in rats.

Swim training affects bone canonical Wnt pathway in type 2 diabetes induced by high fat diet and low dose of streptozotocin in male rats.

Objective: Susceptibility to diabetes-induced bone complication has been linked to Wnt signaling, which plays an important role in bone development and remodeling. In this study, the effect of swim training on Wnt pathway in T2DM was investigated. Materials and methods: Forty male rats were assigned to groups: control (C), diabetic (D), exercised control (E) and diabetic exercised (DE). One week after the induction of diabetes, animals were subjected to swim. At the end of training, bone gene and protein levels of SOST, RUNX2 and RANKL/OPG ratio were measured. Results: Diabetes could significantly increase bone sclerostin expression levels, while decreased RUNX2 mRNA and protein. Bone RANKL/OPG ratio was significantly lower in diabetic rats compared to control group. Swim training significantly increased this ratio in DE compared to D group. Conclusion: Swim training could partially compensate the diabetes-associated changes of Wnt pathway possibly by moderating sclerostin or blood sugar.

The effect of date palm seed extract as a new potential radioprotector in gamma-irradiated mice.

OBJECTIVE: Date palm seed extract (DPSE) has various compounds revealing antioxidant features. This study aimed to evaluate the radioprotective effect of DPSE in total body gamma irradiation. MATERIALS AND METHODS: At first, chemical characteristics of DPSE were analyzed by ultraviolet, visible and Fourier transform infrared spectroscopy. Then, the toxicity of DPSE was assessed. For this purpose, 60 mice were divided into five groups, and each of the groups were injected by the doses of 100, 200, 300, 400, and 500 mg/kg, respectively. At the termination of the experiment, mortality rate and weight loss of all mice were evaluated over a period of 30 days. Finally, the radioprotective effect of DPSE was evaluated by dividing 36 mice into three groups: control, test, and placebo and then were irradiated by Cobalt-60. RESULTS: According to the findings, there was no mortality due to DPSE. Furthermore, for the maximum dose of 500 mg/kg, the number of mice surviving at the termination of the experiment with and without injection of DPSE was reported as 83% and 41%, respectively. In addition, a significant difference was obtained between radiated mice with and without DPSE injection (P = 0.035). CONCLUSION: The findings showed that DPSE injected into mice before irradiation has no toxicity and could protect mice from lethal effects of total body irradiation. The use of DPSE as a new radioprotector agent in the human needs further studies, particularly clinical trials.