Biology subjects

Biessen, E. A.

Publications and source records attributed to Biessen, E. A..

3 recordsLinked to original sources

bioRxiv2026

The lipid landscape shapes the immunomodulatory potential of fluoxetine in macrophages

Treatment-resistant depression (TRD) affects approximately one-third of depressed patients, yet the molecular mechanisms underlying this therapeutic non-responsiveness remain unclear. Pharmacological antidepressants, such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine, exert immunomodulatory effects, partially by shifting macrophages towards an anti-inflammatory phenotype. Clinical aberrations in lipid metabolism have been associated with fluoxetine non-responsiveness in depressed populations. As macrophage polarization is highly sensitive to changes in lipid metabolism, pathological alterations in lipid metabolism may directly interfere with the therapeutic efficacy of SSRIs such as fluoxetine. However, how metabolic and immunomodulatory effects of antidepressants relate to each other in the context of TRD remains largely unexplored. We studied the interplay between immunomodulatory capacity of fluoxetine and the macrophage lipid landscape. Human monocyte-derived macrophages (MoDMs) and murine bone marrow-derived macrophages (BMDMs) were utilized as experimental models to evaluate these localized immunometabolic effects. Under baseline conditions in wild-type macrophages, the characteristic anti-inflammatory effect of fluoxetine coincided with distinct intracellular lipid accumulation. Conversely, disrupting this lipid environment yielded opposite immunological outcomes. BMDMs deficient in the low-density lipoprotein receptor (Ldlr-/-) or wild-type BMDMs exposed to inflammatory oxidized phosphocholine-containing phospholipids (OxPLs) failed to undergo anti-inflammatory polarization and exhibited a robust pro-inflammatory response upon fluoxetine treatment instead. Collectively, these data demonstrate a critical link between the macrophage lipid landscape and immunomodulatory efficacy of fluoxetine. These findings suggest that deficiencies in the endogenous LDLR pathway and exposure to circulating lipid peroxidation products can modulate the immunological response to fluoxetine. Our observations highlights microenvironmental lipid stress as a potential contributor to the underlying biology of antidepressant resistance in TRD.

immunology↗

bioRxiv2026

Atherosclerotic plaque iron accumulation characterizes a distinct phase of intra-plaque hemorrhage and is associated with inflammation and remodeling

Intraplaque haemorrhage (IPH) is a hallmark of advanced atherosclerosis and a major risk factor for ischemic stroke and myocardial infarction. Current IPH classification focusses on extravascular erythrocyte presence as a proxy of acute bleeding, where iron detection generally indicates older haemorrhages. While often used interchangeably, a comprehensive analysis of transcriptional and metabolic context and impact of iron and erythrocyte deposition on the plaque is still lacking. Here, we investigate iron as a late-stage IPH hallmark in human atherosclerotic plaques. We analysed erythrocyte-rich, iron-rich, and non-IPH regions in human carotid endarterectomy plaques by re-analysing a published transcriptomic dataset of 43 patient samples. In addition, we performed histological and immune phenotyping to define plaque traits associated with iron versus erythrocyte accumulation. Finally, we performed spatial metabolic profiling to functionally define iron-rich regions. Although iron and erythrocyte deposits frequently co-localised, both co-related with different histological traits. While iron- and erythrocyte-rich regions shared transcriptomic features of advanced plaques compared with non-IPH regions, direct comparison showed differences in gene expression profiles. Iron deposition was associated with increased myeloid cell accumulation and a unique spatial metabolic signature distinct from erythrocyte-rich and non-IPH regions. While sharing many characteristics with IPH plaques, the molecular, cellular and metabolic landscape of iron-rich regions is marked by features of plaque remodelling and repair. This makes iron deposition a unique hallmark of late-stage IPH, extending the current erythrocyte-based definition of IPH.

pathology↗

bioRxiv2020

Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Conclusion: Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.

neuroscience↗