Chemerin-induced macrophages pyroptosis in fetal brain tissue leads to cognitive disorder in offspring of diabetic dams

Abstract

BackgroundChemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear.MethodsA diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes.ResultsChemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1β) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam’s offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams’ offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams.ConclusionsChemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1573-6) contains supplementary material, which is available to authorized users.

The m6A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

“…Group 3 showed reduced secretion of proteins known to restrict infection such as (i) the pro-inflammatory factors IL33 and RBP4 (Liu et al, 2017; Xu et al, 2019), (ii) activators of the inflammasome (e.g. CHEMERIN (Liang et al, 2019)), the respiratory burst (e.g. CCL2, (Rollins et al)), the classical complement cascade (e.g.…”

Chemerin-Induced Down-Regulation of Placenta-Derived Exosomal miR-140-3p and miR-574-3p Promotes Umbilical Vein Endothelial Cells Proliferation, Migration, and Tube Formation in Gestational Diabetes Mellitus

“…A typical diabetic model was established by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) for five consecutive days, beginning three days after pregnancy [ 29 ]. The chemerin-induced maternal diabetic model was established by intraperitoneal injection of chemerin (3–4 μg/g body weight, 2325-CM, RD, MN, USA) at gestational day (GD) 2, for three consecutive days [ 20 ], and the control group by intraperitoneal injection with normal saline at the same time. Both groups were verified by measuring fasting blood glucose (FBG) and fasting blood insulin levels (FBINS) at GD 10.5 and 18.5 using enzyme-linked immunosorbent assay (ELISA) kits (FBG, S0201S, Beyotime, Shanghai, China; FBINS, E-EL-M1382c, Elabscience, Wuhan, China) and the homeostasis model of assessing insulin resistance (HOMA-IR) ( Figure S1 ).…”

“…Previous studies have shown that levels of chemerin were higher in the blood, placental tissue, and cord blood of diabetic pregnancy patients [ 18 , 19 ]. Aggregation of chemerin led to macrophage recruitment and the release of inflammatory cytokines in the brains of offspring from chemerin-treated GDM dams [ 20 ]. However, whether chemerin has a role in regulating the function of fetoplacental endothelial cells in GDM has yet to be confirmed.…”

Advances in the Relationship Between Pyroptosis and Diabetic Neuropathy

“…They found that Naofucong can significantly inhibit the P2 × 7R/NLRP1/caspase-1 pathway and improve the HT22 hippocampal neuron damage induced by high glucose ( Jing et al, 2021 ). Furthermore, in the studying of the gestational diabetes, it was showed that the aggregation of chemotactic proteins in the offspring’s brain tissue induces the neuronal loss, increases the aggregation of macrophages, and activates the pyroptosis of macrophages in a ChemR23-dependent manner, which leads to neurological damage and cognitive impairment in the offspring ( Liang et al, 2019 ). In a word, DE is an extremely complicated process, and the specific role of pyroptosis in various of encephalopathy needs to be further explored ( Table 1 ).…”