Biology subjects

Huby, T.

Publications and source records attributed to Huby, T..

8 recordsLinked to original sources

bioRxiv2026

Increased expression of Cd74 and MHC II genes by aortic macrophages links atherosclerosis with aging in mice

Atherosclerosis is a chronic inflammatory condition of the arteries leading to myocardial infarction, ischemic stroke and peripheral arterial diseases. Atherosclerotic plaques, which obstruct blood flow contain functionally diverse macrophage populations including pro-atherogenic and atheroprotective subsets. Aging is a major risk factor of atherosclerosis, but the mechanism underlying aging associated risk of atherosclerosis is unclear. Here, using integrated single-cell RNA sequencing data analysis, we demonstrate that specific monocyte and macrophage subsets are enriched in atherosclerotic plaques and the aging aorta of mice. We also show that Cd74 and MHCII genes such as H2-Aa, H2-Ab1, H2-Eb1, and H2-DMb1 are consistently upregulated in the monocytes and macrophages from atherosclerotic plaques, the aging aorta, and the aging bone marrow of mice. Our experimental data also show increased expression of CD74 surface protein by aortic macrophages and bone marrow monocytes from aged mice. In addition, we show increased CD74 expression by RAW264.7 mouse macrophages and THP1 human monocytes following ox-LDL stimulation in vitro. Finally, we demonstrate that monocytes from aged mice adhere more to aortic endothelial cells in co-cultures. Thus, increased monocyte adhesion to endothelial cells may explain the enhanced proportion of specific monocyte and macrophage subsets in the aging aorta, inducing a pre-atherosclerotic condition.

immunology↗

bioRxiv2026

CD14 and and TLR4 contribute to the circadian regulation of retinal phagocytosis as co-receptors

Retinal pigment epithelium (RPE) cells perform crucial functions for vision, among which the daily clearance of photoreceptor outer segment (POS) oxidized extremities. POS phagocytosis is under circadian regulation, peaking only once a day despite the constant contact between both cell types. Alphavbeta5 integrin receptors and MFG-E8 ligands synchronize POS phagocytosis and activate the MerTK internalization receptor via an intracellular signaling cascade. Recently, we identified scavenger receptors CD36 and SR-B2/LIMP2 as POS internalization regulators. We now highlight that innate immunity receptors CD14 and TLR4 interact with POS as stimulatory coreceptors in a tissue-specific fashion. CD14 and TLR4 associate partially with lipid rafts, and their activation triggers MyD88-dependent JNK and ERK1/2 (p44/42) kinases. In vivo, CD14 and TLR4 protein levels are replenished in the hours leading to the phagocytic peak. In addition, the phagocytic peak is lost in Tlr4-/- RPE cells, thus confirming that TLR4 regulates this function. Finally, CD14 and TLR4 associate with SR-B2, partner with CD36 and MerTK, highlighting that several receptors contribute together to the fine regulation of POS phagocytosis as a macromolecular machinery.

cell biology↗

bioRxiv2023

Obesity-elicited macrophages shape CD9hi progenitor fate to promote adipose tissue fibrosis and dysfunction

Obesity is a life-threatening condition characterized by a maladaptive remodeling of the visceral white adipose tissue (vWAT), including fibrosis, that drives vWAT metabolic alterations. We previously identified CD9hi adipose tissue progenitors as the main drivers of vWAT fibrosis in mice and humans. However, how their functions are controlled, especially by macrophages, remains largely unknown. We found that obesity-elicited monocyte-derived macrophages (obeMac) accumulation was considerably elevated in mice prone to obesity-induced vWAT fibrosis. Limiting obeMac build-up decreased the numbers and fibrogenic activation of CD9hi progenitors, leading to decreased vWAT fibrosis and improved glucose homeostasis. In patients with obesity, we identified macrophages similar to mouse obeMacs that were associated with accumulation of CD9hi progenitors in the vWAT and loss of glycemic control. Finally, intercellular communication analysis identified mediators produced by obeMacs that control the fibrogenic potential of CD9hi progenitors. Together, we uncovered an obeMac-CD9hi progenitors axis controlling vWAT fibrosis and dysfunction.

pathology↗

bioRxiv2023

Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development

Hypercholesterolemia is a major risk factor for atherosclerosis and associated cardiovascular diseases. The liver plays a key role in the regulation of plasma cholesterol levels and hosts a large population of tissue-resident macrophages known as Kupffer cells (KCs). KCs are located in the hepatic sinusoids where they ensure key functions including blood immune surveillance. However, how KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins that occurs in the circulation during hypercholesterolemia remains unknown. Here, we found that embryo-derived KCs (EmKCs) accumulated large amounts of lipoprotein-derived cholesterol, in part through the scavenger receptor CD36, and massively expanded early after the induction of hypercholesterolemia. After this rapid adaptive response, EmKCs exhibited mitochondrial oxidative stress and their numbers gradually diminished while monocyte-derived KCs (MoKCs) with reduced cholesterol-loading capacities seeded the KC pool. Decreased proportion of EmKCs in the KC pool enhanced liver cholesterol content and exacerbated hypercholesterolemia, leading to accelerated atherosclerotic plaque development. Together, our data reveal that KC homeostasis is perturbed during hypercholesterolemia, which in turn alters the control of plasma cholesterol levels and increases atherosclerosis.

pathology↗

bioRxiv2023

Dietary fibers benefits on glucose homeostasis require type 2 conventional dendritic cells in mice fed a high-fat diet

Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity. Here, we observed that short-term HFD induced dysbiosis, glucose intolerance and decreased intestinal ROR{gamma}t+ CD4 T cells, including peripherally-induced Tregs and IL17-producing (Th17) T cells. However, dietary fiber supplementation of HFD-fed animals was sufficient to maintain ROR{gamma}t+ CD4 T cell subsets and microbial species known to induce them, alongside having a beneficial impact on glucose tolerance. Dietary fiber-mediated normalization of Th17 cells and amelioration of glucose handling required the cDC2 dendritic cell subset in HFD-fed animals, while IL-17 neutralization limited fibers impact on glucose tolerance. Overall, we uncover a novel and pivotal role of cDC2 in the control of the immune and metabolic effects of dietary fibers in the context of HFD feeding.

immunology↗

bioRxiv2022

Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.

immunology↗

bioRxiv2020

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet. Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses. Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

immunology↗

bioRxiv2020

Molecular determinants of SR-B1-dependent Plasmodium sporozoite entry into hepatocytic cells.

Sporozoite forms of the malaria parasite Plasmodium are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. The molecular mechanisms involved during sporozoite invasion of hepatocytes remain poorly understood. Two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the scavenger receptor class B type 1 (SR-B1), play an important role during the entry of Plasmodium sporozoites into hepatocytic cells. In contrast to HCV entry, which requires both CD81 and SR-B1 together with additional host factors, CD81 and SR-B1 operate independently during malaria liver infection. Sporozoites from human-infecting P. falciparum and P. vivax rely respectively on CD81 or SR-B1. Rodent-infecting P. berghei can use SR-B1 to infect host cells as an alternative pathway to CD81, providing a tractable model to investigate the role of SR-B1 during Plasmodium liver infection. Here we show that mouse SR-B1 is less functional as compared to human SR-B1 during P. berghei infection. We took advantage of this functional difference to investigate the structural determinants of SR-B1 required for infection. Using a structure-guided strategy and chimeric mouse/human SR-B1 constructs, we could map the functional region of human SR-B1 within apical loops, suggesting that this region of the protein may play a crucial role for interaction of sporozoite ligands with host cells and thus the very first step of Plasmodium infection. IMPORTANCEMalaria is caused by Plasmodium parasites and remains one of the deadliest parasitic diseases worldwide. The parasite is transmitted by a blood feeding mosquito and first invades the liver for an initial, obligatory and silent round of replication. The liver infection is an attractive target for antimalarial vaccine strategies, however the molecular mechanisms of parasite invasion of hepatocytes remain to be fully elucidated. Two hepatocyte surface proteins are known to be important for parasite entry into hepatocytes, the tetraspanin CD81 and the scavenger receptor class B type 1 (SR-B1). These receptors constitute independent gateways depending on the Plasmodium species. Here, we identified the structural determinants of SR-B1, an important hepatocyte entry factor for human-infecting P. vivax. This study paves the way toward a better characterization of the molecular interactions underlying the crucial early stages of infection, a pre-requisite for the development of novel malaria vaccine strategies.

microbiology↗