A Protective Role of Tumor Necrosis Factor Superfamily-15 in Intracerebral Hemorrhage-Induced Secondary Brain Injury

Abstract

Destabilization of blood vessels by the activities of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) following intracerebral hemorrhage (ICH) has been considered the main causes of aggravated secondary brain injury. Here, we show that tumor necrosis factor superfamily-15 (TNFSF15; also known as vascular endothelial growth inhibitor), an inhibitor of VEGF-induced vascular hyper-permeability, when overexpressed in transgenic mice, exhibits a neuroprotective function post-ICH. In this study, we set-up a collagenase-induced ICH model with TNFSF15-transgenic mice and their transgene-negative littermates. We observed less lesion volume and neural function perturbations, together with less severe secondary injuries in the acute phase that are associated with brain edema and inflammation, including vascular permeability, oxidative stress, microglia/macrophage activation and neutrophil infiltration, and neuron degeneration, in the TNFSF15 group compared with the littermate group. Additionally, we show that there is an inhibition of VEGF-induced elevation of MMP-9 in the perihematomal blood vessels of the TNFSF15 mice following ICH, concomitant with enhanced pericyte coverage of the perihematomal blood vessels. These findings are consistent with the view that TNFSF15 may have a potential as a therapeutic agent for the treatment of secondary injuries in the early phase of ICH.

Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption

“…ARDS involves the transient disruption of the epithelial barrier, which can be spontaneously repaired or eventually progress to fibrosis [ 32 ]. The current results support the findings of Jia et al [ 19 ], Yang et al [ 20 ], Li et al [ 21 ], and Shimodaira et al [ 33 ]. Therefore, the TL1A/DR3 axis can be regarded as a double-edged sword, which is of great significance in guiding the clinical application of TL1A drugs.…”

“…In addition, by using a proteomics approach, the results showed that TL1A KO attenuated MMP-9 expression in an LPS-induced ARDS model. These results are consistent with those of Yang, in which VEGF-induced increase in MMP-9 in peripheral blood vessels was inhibited in TL1A-transgenic mice after intracerebral hemorrhage [ 20 ]. The differences in results could be explained by differences in the mouse disease model and the distribution of TL1A in mice.…”

“…A novel role for TL1A/DR3 in protection against intestinal injury was reported by Jia et al [ 19 ]. Yang et al revealed the protective effect of TL1A against intracerebral hemorrhage-induced secondary brain injury and infection [ 20 ]. In addition, Li et al confirmed that TL1A maintains the blood–retina barrier by modulating SHP-1-Src-VE-cadherin signaling in diabetic retinopathy [ 21 ].…”

Immune Checkpoint Inhibitor (ICI) Genes and Aging in Clear Cell Renal Cell Carcinoma (ccRCC): Clinical and Genomic Study

“…The literature has reported this new gene TNFSF15 and its role in angiogenesis and inflammation but does not describe it is clinical efficacy in RCC and/or associated immune cells, principally in aging. Multifaceted cytokine tumor necrosis factor superfamily-15 (also known as VEGI15 or TL1A16) is mostly released by endothelial cells in existing blood channels [ 38 ], where it then leads to the inhibition of new blood vessels [ 39 , 40 , 41 ]. Some studies have shown that high TNFSF15 levels in cancers decrease the growth of the tumor [ 42 , 43 ].…”

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

“…In particular, PAR1 and PAR4 play a pivotal role as thrombin receptors in the various hemorrhagic diseases of the nervous system such as cerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) (Ye et al, 2021). Activated microglia after intracerebral hemorrhage can directly secrete matrix metalloproteinase (MMP), MMP-2 and MMP-3, which can significantly damage the blood-brain barrier (Zhu et al, 2016;Yang et al, 2021). At the same time, TNF-α and other inflammatory factors can be released to induce the activation of MMP-9 to promote the degradation the vascular wall matrix, and increase the permeability of BBB (Müller et al, 2021).…”