Homéostasie | EPFL Graph Search

En biologie et en systémique, l’homéostasie est un phénomène par lequel un facteur clé (par exemple, la température) est maintenu autour d'une valeur bénéfique pour le système considéré, grâce à un processus de régulation. Des exemples typiques d'homéostasie sont : la température d'une pièce grâce à un thermostat, la température du corps d'un animal homéotherme, le taux de sucre sanguin, le degré d'acidité d'un milieu, la pression interne d'un milieu, etc. Plus globalement, on désigne aussi par homéostasie la capacité globale d'un système à maintenir tout un ensemble de tels facteurs clés, notamment chez un organisme vivant. Opérant comme un système de régulation, l’homéostasie requiert un capteur (naturel ou artificiel) qui mesure le facteur réel, un actionneur capable d'agir sur sa valeur, et entre les deux un processus d'ajustement permettant de faire varier l'activité de l'actionneur en fonction de la valeur mesurée. En automatisme, il s'agit d'un centre de contrôle quelconque (

An Exploratory Study On The Functional Significance Of Eosinophil Residency In The Small Intestine Under Homeostatic Conditions

Kathleen Shah

The small intestine is a highly dynamic and complex cellular ecosystem, which serves as the primary interface between the host and its environment. A critical component of this ecosystem is the microbiota, which plays a pivotal role in shaping both immune and physiological homeostasis of the host from the moment of birth. However, interaction with the microbiota is a double-edged sword â and the inappropriate establishment of host-microbiota crosstalk could lead to detrimental consequences. Eosinophils are multi-functional granulocytes, recruited into the intestine in early life â but the relevance of this phenomenon has remained enigmatic, given the dogmatic view of these cells as drivers of pathophysiology in type-II immune mediated disorders. Understanding the functional significance of their residency in this tissue under homeostatic conditions warrants further investigation and may provide invaluable insight into their dysregulation in disease. In this thesis, I report our investigation of the contributions of eosinophils to small intestinal homeostasis through a broad characterization of changes in various intestinal functions consequent of eosinophil-deficiency. We approached this expansive question through a combination of histological, cellular and transcriptional analyses, which have afforded us unprecedented insight to eosinophil function in this tissue. Using Îdbl.GATA1 mice, a model of constitutive eosinophil deficiency, we provide evidence for a central role for eosinophils in tissue integrity maintenance in response to the microbiota. We report herein that eosinophil-mediated tissue protection is largely driven by epithelial-derived alarmins, released in response to barrier stress â which equips eosinophils with the capacity to maintain small intestinal integrity and homeostasis through the regulation of extracellular matrix remodelling. In summary, our work provides a functional rationale for the early life recruitment of eosinophils in the small intestine, implicating these cells as key facilitators in the establishment of appropriate host-microbiota crosstalk.

EPFL2018

Characterization of STAT1-/- mice & Investigation of IFN alpha/beta production in murine bone marrow in response to injury

Yulia Kirpicheva

The hematopoietic system is a regenerative tissue with high cell turnover. Normal homeostasis of the hematopoietic system is insured by hematopoietic stem cells (HSCs). The important features of HSCs are the capacity to self-renew and multipotency. Multipotent HSCs perpetuate through life and are able to form all differentiated cell lineages of the blood. Most HSCs with long-term self-renewal capacity are quiescent and divide infrequently. However quiescent HSCs can be activated in response to injury. The signals responsible for the activation of quiescent HSCs are poorly investigated. The Trumpp laboratory has recently identified a role for IFNα in activation of quiescent HSCs in vivo. Activation of HSCs by IFNα involves increased phosphorylation of STAT1. Therefore the role of STAT1 in the homeostasis of the hematopoietic system was investigated by characterization of the hematopoietic system in STAT1-/- mice. A 2-fold decrease in short-term HSC (ST-HSCs) and multipotent progenitors (MPPs) was observed in the bone marrow of STAT1-/- mice compared to C57Bl/6 (wild type) mice. Analysis of progenitors of HSCs also revealed a small increase in common myeloid progenitors (CMPs) and a small decrease in common lymphoid progenitors (CLPs) in the bone marrow of STAT1-/- mice. These results indicate that STAT1 play a role in the homeostasis of ST-HSCs and MPPs in bone marrow. Functional analysis of STAT1-/- LT-HSCs using in vivo long-term reconstitution assay suggests that STAT1-/- LT-HSCs can reconstitute lethally irradiated mice. Nevertheless further investigations are necessary to examine whether STAT1 plays a role in HSCs self-renewal. The unexpected role of IFNα in activation of quiescent HSCs leads to the hypothesis that endogenously produced IFNα might be important for activation of HSCs in response to injury. To address this we generated the mouse model MxCre;R26REYFP to monitor endogenous IFNα/β production in the bone marrow after injury. Our results suggest that IFNα/β is produced in response to 5-FU induced myeloid suppression and G-CSF treatment in vivo. The role of IFNα/β during the recovery phase after 5-FU induced myeloid suppression was investigated using IFNAR-/- mice. These results suggest that endogenous IFNα/β might be important for the mobilization of HSCs into the spleen induced in response to 5-FU

2008

Mitochondrial respiratory chain dysfunction disrupts intracellular cholesterol homeostasis

Christopher Tadhg James Wall

Mitochondrial diseases are rare and severe conditions with debilitating symptoms. Biochemical defects in mitochondria however are common. The difference between these two frequencies is suspected to lie in the capability of the cells to adapt to the homeostatic disbalance. Cells activate retrograde signalling pathways in response to mitochondrial dysfunction, activating cellular transcriptional programs to correct for the disbalance. The full extent of the retrograde signals that are induced by mitochondrial dysfunctions still remains unknown. Studying these retrograde signalling pathways can lead to insights how to make the difference between restoring the homeostasis and a detrimental disease. Investigating the transcriptional responses to artificially induced mitochondrial dysfunction has proven to be lucrative in unveiling novel responses to mitochondrial defects. In this work we studied the transcriptional responses to three chemical models of mitochondrial respiratory chain dysfunction. In line with recently published work, we found a commonly upregulated stress response in all models. Interestingly, shared between all the models was a downregulation of genes enriched in cholesterol biosynthesis pathways. Upon closer examination this encompassed, almost without exception, all transcripts of the mevalonate pathway. This coordinated downregulation of transcripts had functional consequences on the output of the pathway, lowering the abundance of cholesterol precursor metabolites. Other metabolites in more upstream regions of the pathway were changed differently depending on the complex affected, suggesting other regulatory influences involved. Upon closer mechanistic investigation to the cause of the transcriptional suppression we found the main transcription factor responsible for mevalonate pathway gene transcription, the Sterol Response Element Binding Protein 2 (SREBP2), to be inhibited during complex I impairment. This was most evident in sterol depleted conditions where SREBP2 did not activate to normal levels. A decreased activation of SREBP2 is signature for an elevated concentration of ER-cholesterol. Indeed, other ER-bound cholesterol sensitive proteins confirmed this, showing a similar decreased abundance following complex I impairment in both normal and low lipid conditions. To investigate the source of this cholesterol we measured various cholesterol levels. No changes in the levels of total cholesterol (free cholesterol plus esterified cholesterol) were detected. Also, the fraction of free cholesterol was not significantly affected by complex I inhibition. Using the fluorescent cholesterol stain filipin, we were able to measure a modest but reproducible increase in intracellular free cholesterol. This provided novel mechanistic insight into the inhibition of ER sterol sensors and mevalonate pathway activity by mitochondrial dysfunction. Several well-known retrograde signalling pathways AMPK, ISR and mTOR did not explain the changes observed. The exact mechanism through which mitochondria incite an increase in intracellular free cholesterol remains unknown. Taken together this work can provide a mechanistic link between mitochondrial function and intracellular cholesterol homeostasis and could possibly link mitochondrial function to circulating lipoprotein homeostasis. Further work should focus on elucidating the possible mechanism, where differences in complex functions could provide a hint in the right direction.

EPFL2022