Biology subjects

Hiyane, M. I.

Publications and source records attributed to Hiyane, M. I..

3 recordsLinked to original sources

bioRxiv2023

Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis

Mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in tissue-resident CD11c+ myeloid cells (CD11cRic{Delta}/{Delta}), this study investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon DSS-induced colitis, lack of mTORC2 signaling CD11c+ cells diminish colonic inflammation, abrogates dendritic cell (DC) migration to the mesenteric lymph nodes (MLN), thereby diminishing the infiltration of T helper (Th) 17 cells in the lamina propria (LP). These findings corroborate with abrogation of cytoskeleton organization and decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis (UC) patients revealed increased gene expression of pro-inflammatory cytokines which coincided with augmented expression of mTOR pathway, positive correlation between the DC marker ITGAX, and IL-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses and this way, ameliorates the progression and severity of intestinal inflammatory diseases.

immunology↗

bioRxiv2021

MS-driven metabolic alterations are recapitulated in iPSC-derived astrocytes

ObjectiveAstrocytes play a significant role in the pathology of Multiple Sclerosis (MS). Nevertheless, for ethical reasons, most of the studies in these cells were performed on the Experimental Autoimmune Encephalomyelitis model. As there are significant differences between human and mouse cells, we aimed here to better characterize astrocytes from patients with MS (PwMS), focusing mainly on mitochondrial function and cell metabolism. MethodsWe obtained and characterized induced pluripotent stem cell (iPSC)-derived astrocytes from three PwMS and three unaffected controls and performed functional assays including electron microscopy, flow cytometry, cytokine measurement, gene expression, in situ respiration, and metabolomics. ResultsWe detected several differences in MS astrocytes including: (i) enrichment of genes associated with mitophagy and neurodegeneration, (ii) increased mitochondrial fission and decreased mitochondrial to nuclear DNA ratio, indicating disruption of mitochondrial content, (iii) increased production of superoxide and MS-related proinflammatory chemokines, (iv) increased electron transport capacity and proton leak, in line with the increased oxidative stress, and (v) a distinct metabolic profile, with a deficiency in amino acid catabolism and increased sphingolipid metabolism, which have already been linked to MS. InterpretationTo our knowledge, this is the first study thoroughly describing the metabolic profile of iPSC-derived astrocytes from PwMS, and validating this model as a powerful tool to study disease mechanisms and to perform non-invasive drug targeting assays in vitro. Our findings recapitulate several disease features described in patients and provide new mechanistic insights into the metabolic rewiring of astrocytes in MS, which could be targeted in future therapeutic studies.

neuroscience↗

bioRxiv2020

Sensing soluble uric acid by Naip1-Nlrp3 platform

The immune system can recognize microbes and sterile tissue damage. Among the damage-associated molecular patterns (DAMPs), uric acid is considered a major component which can trigger inflammation. It represents a breakpoint in the evolutionary history of humans as our ancestors lost the uricase gene, the enzyme responsible for its cleavage. High soluble uric acid (sUA) concentration is able to increase IL-1{beta} in murine, but not human macrophages. We observed that sUA increased the mRNA expression of Naip1 in murine macrophages, and, therefore, we hypothesized that the recognition of sUA can be made by a Naip1-Nlrp3 inflammasome platform. Additionally, we used genome-wide transcriptome analysis, functional analyses and structural modeling predictions and observed that virus-transduction of murine Naip1 into human macrophages induced IL-1{beta} after sUA stimulus, besides leading to fatty acid production and an inflammation-related response. Moreover, pharmacologic inhibition and genetic loss of Nlrp3 led to decreased IL-1{beta} production upon sUA stimulus. Surface plasmon resonance and quartz crystal microbalance showed that sUA is able to interact with Naip1. Naip could be a lost receptor for sUA in the evolutionary process and a better understanding of the immune modulatory function of sUA could lead to design rational novel anti-hyperuricemic therapies.

immunology↗