Biology subjects

Bensussan, A.

Publications and source records attributed to Bensussan, A..

3 recordsLinked to original sources

bioRxiv2026

CD160 is an inducible endothelial checkpoint that suppresses sprouting angiogenesis through LRP1-dependent autophagy

Pathological angiogenesis is a hallmark of cancer and other chronic diseases, yet therapeutic strategies remain largely focused on blocking pro-angiogenic signals rather than restoring endogenous mechanisms that restrain endothelial sprouting. The identification of endothelial checkpoints capable of limiting pathological vessel growth therefore remains an important unmet need. CD160 is a glycosylphosphatidylinositol-anchored immunoglobulin-superfamily receptor of cytotoxic lymphocytes and an inhibitory checkpoint receptor on CD4 T cells. It is also present on endothelium and has been targeted therapeutically. Here, we identify CD160 as an inducible endothelial checkpoint that emerges in response to pro-angiogenic cues and limits pathological angiogenesis. CD160 is absent in resting endothelium. It is induced by basic fibroblast growth factor (bFGF) and most strongly by combining VEGF-A and bFGF, and it is detected in the sprouting region of ex vivo mouse aortic rings. Targeting of CD160 using monoclonal antibody reduces tubulogenesis, scratch closure and aortic-ring sprouting, and softens the cell cortex, while viability and membrane integrity remain intact. Mechanistically, CD160 associates with the endocytic receptor LRP1 as demonstrated by proximity ligation assay, lipid-raft co-immunoprecipitation and super-resolution fluorescence microscopy. Both receptors appear in a common complex, and two independent computational methods converge on the first ligand-binding cluster of LRP1 as the interface. Silencing CD160 or LRP1 abolishes the anti-angiogenic response mediated by the antibody. Under a chloroquine clamp, engagement raises autophagic flux in a CD160- and LRP1-dependent manner, and lysosomal or LDL-receptor-family blockade removes the anti-sprouting effect. CD160 therefore acts as an inducible endothelial checkpoint that suppresses sprouting through autophagic flux. Thus, CD160 represents an inducible endothelial checkpoint that is activated in a pro-angiogenic environment, and targeting CD160 restrains pathological angiogensis.

immunology↗

bioRxiv2024

Deep analysis of the Major Histocompatibility Complex associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS

IntroductionWe have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). MethodsA genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR. Results2,626 SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396. ConclusionOur results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with a partially functional NK cell response which could also explain this markers involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region.

immunology↗

bioRxiv2023

Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells.

Caspase-8 deficiency in the epidermis (caspase-8EKO) results in cutaneous inflammation resembling pustular psoriasis, triggered by necroptotic cell death of keratinocytes. Necroptosis is a highly proinflammatory form of programmed necrosis due to the release of intracellular molecules called alarmins, which can act as inflammatory mediators. However, their role in necroptosis-induced skin inflammation remains unexplored. Here, we demonstrate that alarmin IL-33 and its receptor ST2 are essential early mediators of necroptosis-induced skin inflammation. Genetic ablation of Il-33 or St2 dramatically delays lesion development and improves survival of caspase-8EKO animals. IL-33 is highly expressed in necroptotic epidermis of caspase-8EKO mice and induces immune cell recruitment in the skin upon keratinocyte necroptosis. Impairment of the IL33-ST2 axis does not affect epidermal necroptosis but reduces the recruitment of TNF-producing infiltrating immune cells and subsequent amplification of cutaneous inflammation. Collectively, our findings highlight a pivotal role for IL-33 and ST2 in necroptosis-induced skin inflammation. TeaserInhibition of IL-33/ST2 axis alleviates necroptosis-induced skin inflammation by reducing TNF production in the dermis.

immunology↗