Biology subjects

Amoura, Z.

Publications and source records attributed to Amoura, Z..

3 recordsLinked to original sources

bioRxiv2024

Mechanism of neurodegeneration mediated by clonal inflammatory microglia

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

immunology↗

bioRxiv2023

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease (NLRP3-AID or CAPS) is an heterogenous group of monogenic autoinflammations associated with NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants is a barrier to diagnosis although patients can be efficiently treated with anti-IL-1 approaches. In addition, while NLRP3 inflammasome is controlled by coordinated priming and activation signals, gain-of-functions of NLRP3 variants have been only investigated in response to priming. Here, we functionally characterize 34 NLRP3 variants in vitro by determining their activity in response to induction, priming and/or activation signals, and their sensitivity to inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on their profile of signals required for their activation, that correlate partly with the symptoms severities. We identify a new group of NLRP3 mutants responding to the activation signal without priming, with patients often misdiagnosed. Our results identify key NLRP3 residues controlling the inflammasome activity and sensitivity to inhibitors. The comparison of four inhibitors on the 34 variants identifies inhibitory mechanisms with broader efficiency for future drug design. Altogether, our results provide new insights on NLRP3 activation and an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and anti-inflammatory disease drug development. eTOC SummaryFunctional characterization of 34 CAPS-associated NLRP3 variants identifies polymorphisms versus gain-of-function pathogenic mutants, and highlights diversities in the signals controlling their activation and in their sensitivity to inhibitors. This study provides tools for CAPS diagnosis and anti-inflammation drug development and insights on NLRP3 control mechanisms.

immunology↗

bioRxiv2020

LOX-1+ immature neutrophils predict severe COVID-19 patients at risk of thrombotic complications

RationalLymphopenia and neutrophil/lymphocyte ratio may have prognostic value in coronavirus disease 2019 (COVID-19) severity. ObjectiveWe sought to investigate the representation of neutrophil subsets in severe and critical COVID-19 patients based on Intensive Care Units (ICU) and non-ICU admission. MethodsWe developed a multi-parametric neutrophil profiling strategy based on known neutrophil markers to distinguish COVID-19 phenotypes in critical and severe patients. ResultsOur results showed that 80% of ICU patients develop strong myelemia with CD10-CD64+ immature neutrophils. Cellular profiling revealed two distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or the Interleukin-3 receptor alpha (CD123), both significantly overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1-expressing immature neutrophils positively correlated with clinical severity, with the cytokine storm (IL-1{beta}, IL-6, IL-8, TNF), and with intravascular coagulation. Importantly, high proportions of LOX-1+-immature neutrophils are associated with high risks of severe thrombosis. ConclusionsTogether these data suggest that point of care enumeration of LOX-1-immature neutrophils might help distinguish patients at risk of thrombosis complication and most likely to benefit from intensified anticoagulant therapy.

immunology↗