Regulation of the Immune Response by the Inflammatory Metabolic Microenvironment in the Context of Allotransplantation

Degauque, Nicolas; Brosseau, Carole; Brouard, Sophie

doi:10.3389/fimmu.2018.01465

Cited by 19 publications

(14 citation statements)

References 114 publications

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“…Many of SRPK3-regulated transcripts encode proteins with functions in cellular metabolism or in the maintenance or biogenesis of mitochondria. In this regard, recent studies confirmed the importance of metabolic reprogramming as a 'gatekeeper' of B lymphocyte development, activation and responses (61)(62)(63)(64)(65). Loss of SRPK3 in MZ B cells results in differential splicing of candidate gatekeepers Nnt and Slc1a5.…”

Section: Discussionmentioning

confidence: 85%

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Arends

Taliaferro

Peterman

et al. 2019

Preprint

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One Sentence Summary: SRPK3 regulates alternative splicing of pre-mRNA that is crucial for B cell development, activation and antibody responses. Abstract:Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo.Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO BM relative to wild-type (WT). Immunization of Srpk3-cKO mice with a T lymphocyteindependent type-2 antigen elicited greatly reduced amounts of specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. We conclude that Srpk3 is an immunomodulatory kinase that controls humoral immunity via its regulation of pre-mRNA splicing, antibody production, and metabolism in B cells. Introduction:Co-transcriptional mechanisms of gene regulation are emerging as important contributors to immune cell differentiation and function. One such mechanism is alternative pre-mRNA splicing (AS), which increases informational diversity, functional capacity, and the efficiency of protein expression (1). Recent studies have confirmed that AS influences immunity and tolerance through its roles in lymphocyte homeostasis (2). Additionally, B cell differentiation, activation, and maturation to antigen secreting cells (ASCs) are dependent on unique splicing patterns that modulate B cell responsiveness and function (3,4). Therefore, understanding how pre-mRNA splicing is regulated in these cells is of critical importance.The functional spliceosome is a dynamic machine comprised of approximately 20 protein and RNA components that regulate splice site selection in pre-mRNAs concurrently with transcription (5, 6). Upstream regulators of splicing include the Serine-Arginine Protein Kinase (SRPK) family, a group of highly conserved serine-threonine kinases that phosphorylate Serine-Arginine repeat (SR)-rich proteins in response to extracellular signals (7-10). SR proteins include splicing factors (SRSF1-12) that promote splice site selection by bridging between initial splice site selection in the pre-spliceosome and assembly of the mature spliceosome.In mammals, SRPK proteins (SRPK1 and SRPK2) have been extensively studied as regulators of AS and mRNA maturation (11-13), transduction of growth signaling (14), chromatin reorganization (15), cell cycle (7) and metabolic signaling (16). However, the function of SRPK3 has not been elucidated. SRPK3 was identified first as a transcriptional target of Myocyte Enhancer Factor 2C (MEF2C) in skeletal muscle and the heart (17). Later studies identified the X-linked ...

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Section: Discussionmentioning

confidence: 85%

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Arends

Taliaferro

Peterman

et al. 2019

Preprint

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“…Anaerobic glycolysis requires a lactate efflux mediated by proton‐coupled symporters or monocarboxylate transporters (MCT) and causes a pH decrease. The low external pH of the extracellular medium induces the inhibition of MCT‐mediated lactate efflux . This results in the accumulation of lactate inside the cells and subsequent inhibition of glycolytic enzyme activity through a feedback mechanism .…”

Section: Resultsmentioning

confidence: 99%

Formulation of survival acceptor medium able to maintain the viability of skin explants over in vitro dermal experiments

Tarnowska

Briançon

Azevedo

et al. 2019

Intern J of Cosmetic Sci

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OBJECTIVE: In vitro assessments of skin absorption of xenobiotics are essential for toxicological evaluations and bioavailability studies of cosmetic and pharmaceutical ingredients. Since skin metabolism can greatly contribute to xenobiotic absorption, experiments need to be performed with skin explants kept viable in suitable survival media. Existing protocols for non-viable skin are modified to consider those conditions. The objective was to design a survival medium used as an acceptor fluid in Franz cells for testing cutaneous penetration of hydrophilic or lipophilic molecules. Their metabolism inside skin may be investigated under the same conditions. The determining factors involved in survival mechanisms in vitro are discussed. The consequences of short-term skin preservation at 4°C were also evaluated. METHODS: The metabolic activity of fresh skin samples mounted in Franz cells was studied by measurement of lactate release over 24 h in order to assess the impacts of pH, buffering, osmolality, ionic strength, initial glucose supply and the addition of ethanol or non-ionic surfactant in the acceptor part of Franz cells. CONCLUSION: Survival media must maintain physiological pH (>5.5) be isotonic with skin cells (300 mOsm kg À1 ) and contain at least 0.5 g L À1 glucose. Several compositions able to preserve skin metabolism are reported. Storage of skin explants overnight at 4°C impairs skin metabolic activity. The present work provides guidelines for designing survival media according to constraints related to the scientific requirements of the experiments.

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“…Excess lactate import into T cells has also been shown to restrict proliferation and cytokine production of CTLs. This is possibly due to their reliance on glycolysis [ 30 ], as lactate import goes along with consumption of reduced nicotinamide adenine dinucleotide (NADH) and inhibition of glycolysis [ 31 ]. On the other hand, Tregs are able to change their metabolism to function in a lactate-high environment, and are therefore unaffected [ 32 ].…”

Section: Expression and Importance Of Metabolite Transporters In Tmentioning

confidence: 99%

Metabolite Transporters as Regulators of Immunity

Weiss

Angiari

2020

Metabolites

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In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. While many metabolites bind specific receptors to induce signaling cascades, some are actively exchanged between cells to communicate, or induce metabolic reprograming. In this review, we give an overview about how active metabolite transport impacts immune cell function and shapes immunological responses. We present some examples of how specific transporters feed into metabolic pathways and initiate intracellular signaling events in immune cells. In particular, we focus on the role of metabolite transporters in the activation and effector functions of T cells and macrophages, as prototype adaptive and innate immune cell populations.

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Regulation of the Immune Response by the Inflammatory Metabolic Microenvironment in the Context of Allotransplantation

Cited by 19 publications

References 114 publications

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Formulation of survival acceptor medium able to maintain the viability of skin explants over in vitro dermal experiments

Metabolite Transporters as Regulators of Immunity

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