Human health is being threatened by environmental microplastic (MP) pollution. MPs were detected in the bloodstream and multiple tissues of humans, disrupting the regular physiological processes of organs. Nanoscale plastics can breach the blood-brain barrier, leading to neurotoxic effects. How MPs cause brain functional irregularities remains unclear. This work uses high-depth imaging techniques to investigate the MPs within the brain in vivo. We show that circulating MPs are phagocytosed and lead these cells to obstruction in the capillaries of the brain cortex. These blockages as thrombus formation cause reduced blood flow and neurological abnormalities in mice. Our data reveal a mechanism by which MPs disrupt tissue function indirectly through regulation of cell obstruction and interference with local blood circulation, rather than direct tissue penetration. This revelation offers a lens through which to comprehend the toxicological implications of MPs that invade the bloodstream.

Bile acids (BAs) play important roles in the context of lipid homeostasis and inflammation. Based on extensive preclinical mouse studies, BA signaling pathways have been implicated as therapeutic targets for cardiovascular diseases. However, differences in BA metabolism between mice and humans hamper translation of preclinical outcomes. Recently, we generated Cyp2c70-/- mice with a human-like BA composition lacking mouse/rat specific muricholic acids. We employed this model to assess the consequences of a human-like BA pool on atherosclerosis and heart function in hypercholesterolaemic mice. We overexpressed a PCSK9 gain-of-function (GOF) mutation in the liver of male Cyp2c70-/- and Cyp2c70+/- control mice, and fed these mice a Western-type diet (WD) for 12 weeks. Cyp2c70-/- mice displayed a hydrophobic BA pool rich in chenodeoxycholic acid. Cyp2c70-/- mice showed reduced hepatic total cholesterol and triglycerides (p < 0.05) combined with lower plasma total cholesterol (p < 0.05) and triglycerides (p = 0.05) due to lower VLDL levels. Circulating white blood cells remained largely unaffected in Cyp2c70-/- mice. Interestingly, we found a trend (p = 0.08) towards smaller atherosclerotic lesions in the aortic root of Cyp2c70-/- mice, but no effect on cardiac morphology or function was observed. To conclude, a human-like BA composition ameliorated PCSK9-GOF-induced hypercholesterolaemia in WD-fed mice which translated into a tendency towards smaller atherosclerotic lesions.
© 2025. The Author(s).

The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr-/- mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the ER activates the inositol triphosphate-3 receptor, CaMKII/JNK, and induces NLRP3 deubiquitylation by BRCC3. An NLRP3 deubiquitylation inhibitor or deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex, suppressed inflammasome activation, neutrophil extracellular trap formation (NETosis), and atherosclerosis in vivo. These results identify a link between the trafficking of cholesterol to the ER, NLRP3 deubiquitylation, inflammasome activation, and atherosclerosis.
Published by Elsevier Inc.

Neutrophil extracellular trap formation (NETosis) increases atherosclerotic plaque vulnerability and athero-thrombosis. However, mechanisms promoting NETosis during atherogenesis are poorly understood. We have shown that cholesterol accumulation due to myeloid cell deficiency of the cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/G1) promotes NLRP3 inflammasome activation in macrophages and neutrophils and induces prominent NETosis in atherosclerotic plaques. We investigated whether NETosis is a cell-intrinsic effect in neutrophils or is mediated indirectly by cellular crosstalk from macrophages to neutrophils involving IL-1β.
We generated mice with neutrophil or macrophage-specific Abca1/g1 deficiency (S100A8CreAbca1fl/flAbcg1fl/fl or CX3CR1CreAbca1fl/flAbcg1fl/fl mice, respectively), and transplanted their bone marrow into low-density lipoprotein receptor knockout mice. We then fed the mice a cholesterol-rich diet. Macrophage, but not neutrophil Abca1/g1 deficiency activated inflammasomes in macrophages and neutrophils, reflected by caspase-1 cleavage, and induced NETosis in plaques. NETosis was suppressed by administering an interleukin (IL)-1β neutralizing antibody. The extent of NETosis in plaques correlated strongly with the degree of neutrophil accumulation, irrespective of blood neutrophil counts, and neutrophil accumulation was decreased by IL-1β antagonism. In vitro, IL-1β or media transferred from Abca1/g1-deficient macrophages increased NETosis in both control and Abca1/Abcg1 deficient neutrophils. This cell-extrinsic effect of IL-1β on NETosis was blocked by an NLRP3 inhibitor.
These studies establish a new link between inflammasome-mediated IL-1β production in macrophages and NETosis in atherosclerotic plaques. Macrophage-derived IL-1β appears to increase NETosis both by increasing neutrophil recruitment to plaques and by promoting neutrophil NLRP3 inflammasome activation.
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Peptidylarginine deiminase 4 (PAD4) is a key regulator of inflammation but its function in infections remains incompletely understood. We investigate PAD4 in the context of malaria and demonstrate a role in regulation of immune cell trafficking and chemokine production. PAD4 regulates liver immunopathology by promoting neutrophil trafficking in a Plasmodium chabaudi mouse malaria model. In human macrophages, PAD4 regulates expression of CXCL chemokines in response to stimulation with TLR ligands and P. falciparum. Using patient samples, we show that CXCL1 may be a biomarker for severe malaria. PAD4 inhibition promotes disease tolerance and may represent a therapeutic avenue in malaria.
© 2021 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.