T cell Ig and mucin domain-containing molecule 3 (Tim-3) has been found to play important roles in autoimmune diseases, but whether Tim-3-mediated engulfment of apoptotic cells is involved in systemic lupus erythematosus (SLE) remains to be elucidated. In this study, we verified the role of human Tim-3 (hTim-3) as the receptor of phosphatidylserine (PS) in human embryonic kidney (HEK)293 cells, which initiated the engulfment of apoptotic cells. Both IgV and the mucin domain of Tim-3 were crucial in the phagocytosis of apoptotic cells, and there existed the key cytoplasmic domain for signal transduction. Alanine at 111, locating around the FG-CC' loop of hTim-3, was necessary for its engulfment of apoptotic cells. In accordance, Tim-3 on CD14 cells negatively correlated with the percentage of peripheral apoptotic cells in control subjects. However, although Tim-3 was significantly increased on CD14 cells in SLE patients, peripheral apoptotic cells remained much higher than those in control subjects. Tim-3 on CD14 cells showed positive correlation with percentage of apoptotic cells and level of dsDNA, indicating the involvement of Tim-3 in SLE. Accordingly, soluble Tim-3 (sTim-3) was significantly increased in plasma of SLE patients, which might contribute to higher expression of a disintegrin and metalloproteinase (ADAM)-10. Pretreatment with both plasma from SLE patients and recombinant sTim-3 greatly inhibited hTim-3-initiated phagocytosis of apoptotic cells. Furthermore, anti-Tim-3 antibody depletion of plasma from SLE patients reversed the decreased phagocytosis of apoptotic cells. Collectively, our data suggest that sTim-3 might play inhibitory roles in impaired Tim-3-mediated clearance of apoptotic cells in SLE.

BackgroundEpstein–Barr virus-associated gastric cancer(EBVaGC)has a unique tumor immune microenvironment. We performed a comprehensive analysis of the tumor-infiltrating immune cells in a cohort of EBVaGC in a Chinese population.MethodsEpstein–Barr encoding region (EBER) in situ hybridization was performed in 1,328 consecutive cases of surgically resected GC. Densities of immune cells, including T cells, B cells, natural killer cells, and macrophages from the patients were calculated after immunohistochemical staining with CD3, CD20, CD57, and CD68 antibodies in tissue microarrays, respectively.ResultsEBVaGC patients accounted for 4.1% (55 of 1,328) cases in the overall population. The average age of patients with EBVaGC was lower than that of non-EBVaGC patients. Histologically, EBVaGC patients exhibited poorly differentiated adenocarcinoma (P = 0.004) and lower frequency of vascular invasion (P = 0.034). The density of CD3+ T lymphocytes (CD3, 23.84 ± 14.49 vs. 12.76 ± 8.93, P < 0.001) and CD68+ macrophages (CD68, 9.73 ± 5.25 vs. 5.44 ± 4.18, P < 0.001) was significantly higher in EBVaGC patients. CD3+ T cell density predicted better 5-year overall survival of EBVaGC patients (P = 0.022).ConclusionsEBVaGC patients were younger with low-differentiated adenocarcinoma and less vascular invasion. Increased infiltration of multiple immune cells affected the prognosis of patients, especially EBVaGC patients with more CD3+ T lymphocytes, who survived longer.

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Endotoxic shock is the primary cause of morbidity and mortality in hospital patients, creating an urgent need to explore the mechanisms involved in sepsis. Our previous studies showed that T-cell immunoglobulin- and mucin-domain-containing molecule-4 (Tim-4) attenuated the inflammatory response through regulating the functions of macrophages. However, the mechanism by which Tim-4 does this has not been fully elucidated. In this study, we found that Tim-4 expression was increased in lipopolysaccharide (LPS)-induced endotoxic shock. Interestingly, the survival rate of mice in the Tim-4 overexpression group was higher than that of the control group after LPS administration. To investigate the function of Tim-4 in LPS-induced inflammation, we further demonstrated that Tim-4 attenuated LPS-induced endotoxic shock by inhibiting cytokine production by macrophages. Blocking expression of Tim-4 and nuclear factor-kappa B (NF-κB) signal inhibition showed that Tim-4 inhibited cytokine production via NF-κB signaling pathway. This study indicates that Tim-4 may exert its immune modulation by regulating inflammatory factor secretion and might act as a novel potential target for inflammatory diseases, especially endotoxic shock.

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Background Hippocampal damage caused by status epilepticus (SE) can bring about cognitive decline and emotional disorders, which are common clinical comorbidities in patients with epilepsy. It is therefore imperative to develop a novel therapeutic strategy for protecting hippocampal damage after SE. Mitochondrial dysfunction is one of contributing factors in epilepsy. Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria, we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE. Methods Pilocarpine was used to induced SE in mice. SE‐generated cognitive decline and emotional disorders were determined using novel object recognition, the tail suspension test, and the open field test. SE‐induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes. The metabolites underlying mitochondrial transplantation were determined using metabonomics. Results The results showed that peripheral administration of isolated mitochondria could improve cognitive deficits and depressive and anxiety‐like behaviors. Exogenous mitochondria blunted the production of reactive oxygen species, proliferation of microglia and astrocytes, and loss of neurons in the hippocampus. The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism. Among potential affected metabolites, mitochondrial transplantation decreased levels of sphingolipid (d18:1/18:0) and methylmalonic acid, and elevated levels of D‐fructose‐1,6‐bisphosphate. Conclusion To the best of our knowledge, these findings provide the first direct experimental evidence that artificial mitochondrial transplantation is capable of ameliorating hippocampal damage following SE. These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy‐associated psychiatric and cognitive disorders.

Background: Obesity is known as a common risk factor of osteoporosis and type 2 diabetes mellitus (T2DM). Perirenal fat, surrounding the kidneys, has been reported to be unique in anatomy and biological functions. Several studies have reported the association between perirenal fat and cardiovascular diseases and metabolic diseases. This study aimed to explore the relationship between perirenal fat and β-C-terminal telopeptides of type I collagen (β-CTX) level in patients with T2DM. Methods: A total of 234 patients with T2DM were enrolled. Some basic and clinical characteristics and laboratory test indicators, especially bone metabolism related indicators, were collected. Perirenal fat thickness (PrFT) was performed by ultrasounds via a duplex Doppler apparatus. Multivariate linear regression models were used to identify the relationship between PrFT and β-CTX levels. Results: The PrFT was significantly correlated with β-C-terminal telopeptides of type I collagen (β-CTX) (r = - 0.14, P < 0.036), parathyroid hormone (iPTH) (r = - 0.18, P ≤ 0.006), and 25 hydroxyvitamin D (25-OH-D) (r = - 0.14, P = 0.001). Multivariate analysis confirmed that the association of PrFT and β-CTX (β = -0.136, P = 0.042) was independent of other variables. Conclusion: This study showed a negatively and independently association between PrFT and β-CTX in subjects with T2DM, suggesting a possible role of PrFT in bone resorption. Follow-up studies and further research are necessary to validate the associations and elucidate the underlying mechanisms.