Dataset Information

Intrauterine inflammation induced white matter injury protection by fibrinogen-like protein 2 deficiency in perinatal mice.

ABSTRACT:

Background

White matter injury (WMI) induced by intrauterine inflammation can cause adverse neurological outcomes. Fibrinogen-like protein 2 (FGL2)/fibroleukin is an important trigger of inflammatory responses and is involved in some cerebral diseases. However, the role of FGL2 in intrauterine inflammation-induced WMI remains unclear.

Methods

Lipopolysaccharide (LPS) was intraperitoneally injected into wild-type and FGL2 knockout mice to induce intrauterine inflammation. Body weight and brain weight of offspring were monitored. Major basic protein (MBP) expression was evaluated to demonstrate the myelination of offspring. To investigate the regulatory mechanism of FGL2, cytokine expression, microglial polarization, and the activation of mitogen-activated protein kinase (MAPK) signaling pathway in the offspring were analyzed.

Results

Upon LPS exposure, FGL2 knockout offspring showed a significant increase in body weight loss. MBP reduction induced by LPS was prevented in FGL2 knockout offspring. Expression levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α, and M1 marker CD86 were suppressed, while the expression levels of anti-inflammatory cytokines IL-10 and M2 marker CD206 were increased. FGL2 deficiency significantly inhibited the phosphorylation of p38MAPK and c-Jun N-terminal kinase (JNK) protein.

Conclusions

FGL2 deficiency can ameliorate WMI induced by intrauterine inflammation, reducing inflammatory cascade and improving hypomyelination, through the regulation of microglial polarization and MAPK signaling pathways.

Impact

Intrauterine inflammation induces WMI leading to severe neurological sequelae. FGL2 plays an important role in the progression of WMI induced by intrauterine inflammation. FGL2 deficiency can protect against WMI by inhibiting p38 MAPK and JNK phosphorylation, regulating microglia polarization, and reducing inflammation response. FGL2 could be a novel molecular target for protecting against WMI induced by intrauterine inflammation.

SUBMITTER: Zhan D

PROVIDER: S-EPMC8249236 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The neurological changes in children living with perinatal HIV (PHIV) on antiretroviral therapy (ART) can be studied at a metabolic level through proton magnetic resonance spectroscopy. While previous studies in children have largely focused on individual metabolite changes, investigating patterns within and across regions of interest can aid in identifying metabolic markers of HIV infection. In this study 76 children with PHIV from the Children with HIV Early AntiRetroviral (CHER) trial, 30 children who were HIV-exposed-uninfected (HEU) and 30 children who were HIV-unexposed (HU), were scanned at the age of 11.6 (sd = 0.3) years using a 3 T Skyra scanner. Metabolite concentrations were quantified within the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM), comparing levels between HIV status groups using linear regression. Factor analysis and logistic regression were performed to identify metabolic patterns characteristic of HIV infection within and across the regions of interest. In the BG region we observed restored metabolic activity in children with PHIV and children who were HEU, despite differences being previously observed at younger ages, suggesting that treatment may effectively reduce the effects of HIV infection and exposure. Elevated MFGM choline levels in children with PHIV are indicative of inflammation. Further, we observed reduced N-acetyl-aspartate (NAA) in the PWM of children with PHIV and children who were HEU, indicating possible axonal damage. Lower levels of PWM creatine in children with PHIV suggest that this may not be a valid reference metabolite in HIV studies. Finally, factor scores for a cross-regional inflammatory factor and a PWM axonal factor, driven by PWM NAA and creatine levels, distinguished children with PHIV from children without HIV (HEU and HU) at 11 years. Therefore, the effects of perinatal HIV infection and exposure continue to be seen at 11 years despite early treatment.