Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Jiang, Shuai; Wei, Yan; Wang, Shizhen Emily; Baltimore, David

doi:10.1016/j.cmet.2017.12.007

Cited by 74 publications

(60 citation statements)

References 50 publications

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“…56 While SLC3A2 pairs with SLC7A5 to form CD98, it can also pair with SLC1A5 to make up the ASCT2 transporter, both of which facilitate the uptake of large neutral amino acids by B cells. 58 In addition to these nutrients, leucine uptake promotes mTORC1 activation in B cells. 53 Through the TCA cycle, glutamine can be used to generate other amino acids such as glutamate and aspartate, citrate for use in lipogenic pathways, and succinate which is oxidized to provide electrons for respiration and ATP generation.…”

Section: Activated B Cellsmentioning

confidence: 99%

“…23 The uptake of both glucose and glutamine are tightly regulated processes and are controlled by expression of the microRNA let-7, which suppresses expression of Hexokinase-2 and c-Myc. 58 In addition to these nutrients, leucine uptake promotes mTORC1 activation in B cells. 59 Thus, activation signals promote nutrient uptake to allow B cells to expand and divide.…”

Section: Activated B Cellsmentioning

confidence: 99%

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Plasma cells: You are what you eat

D'Souza

Bhattacharya

2019

Immunological Reviews

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Summary Plasma cells are terminally differentiated B lymphocytes that constitutively secrete antibodies. These antibodies can provide protection against pathogens, and their quantity and quality are the best clinical correlates of vaccine efficacy. As such, plasma cell lifespan is the primary determinant of the duration of humoral immunity. Yet dysregulation of plasma cell function can cause autoimmunity or multiple myeloma. The longevity of plasma cells is primarily dictated by nutrient uptake and non‐transcriptionally regulated metabolic pathways. We have previously shown a positive effect of glucose uptake and catabolism on plasma cell longevity and function. In this review, we discuss these findings with an emphasis on nutrient uptake and its effects on respiratory capacity, lifespan, endoplasmic reticulum stress, and antibody secretion in plasma cells. We further discuss how some of these pathways may be dysregulated in multiple myeloma, potentially providing new therapeutic targets. Finally, we speculate on the connection between plasma cell intrinsic metabolism and systemic changes in nutrient availability and metabolic diseases.

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Section: Activated B Cellsmentioning

confidence: 99%

Section: Activated B Cellsmentioning

confidence: 99%

Plasma cells: You are what you eat

D'Souza

Bhattacharya

2019

Immunological Reviews

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“…In the periphery, let-7 miRNA expression is required for the survival and maintenance of the quiescent phenotype in naïve T cells (28,29). During lymphocyte activation, let-7 miRNAs have been shown to inhibit the metabolic reprogramming of both B cells and CD8 + T cells by negatively regulating the expression of the transcription factor c-Myc and the enzyme hexokinase 2 (28,30). Moreover, let-7 miRNAs have been shown to play a regulatory role in CD8 + cytotoxic T lymphocyte (CTL) function by directly targeting the transcription factor Eomesodermin, as well as in CD4 + helper T cell responses during HIV infection and airway inflammation by regulating the expression of the cytokines IL-10 and IL-13, respectively (28,(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis

et al. 2020

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Multiple sclerosis (MS) is a disabling demyelinating autoimmune disorder of the central nervous system (CNS) which is driven by IL-23-and IL-1β-induced autoreactive Th17 cells that traffic to the CNS and secrete proinflammatory cytokines. Th17 pathogenicity in MS has been correlated with the dysregulation of microRNA (miRNA) expression, and specific miRNAs have been shown to promote the pathogenic Th17 phenotype. In the present study, we demonstrate, using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), that let-7 miRNAs confer protection against EAE by negatively regulating the proliferation, differentiation and chemokine-mediated migration of pathogenic Th17 cells to the CNS. Specifically, we found that let-7 miRNAs may directly target the cytokine receptors Il1r1 and Il23r, as well as the chemokine receptors Ccr2 and Ccr5. Therefore, our results identify a novel regulatory role for let-7 miRNAs in pathogenic Th17 differentiation during EAE development, suggesting a promising therapeutic application for disease treatment.

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“…MicroRNAs (miRs) are short noncoding RNAs of ∼22 nt that are involved in the complex posttranscriptional regulatory networks that control cellular functions such as inflammation and metabolism (8,9). MiR let-7 clusters have been identified as an important contributor to many physiological and pathological processes, for instance, tumorigenesis and B cell antibody production (10)(11)(12). However, the role of miRs in regulating Tet gene expression remains unclear.…”

mentioning

confidence: 99%

Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages

Jiang

Wei

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Tet methylcytosine dioxygenase 2 (Tet2) is an epigenetic regulator that removes methyl groups from deoxycytosine residues in DNA. Tet2-deficient murine macrophages show increased lipopolysaccharide (LPS)-induced and spontaneous inflammation at least partially because Tet2 acts to restrain interleukin (IL)-1β and IL-6 expression in induced cells. MicroRNAs have emerged as critical regulatory noncoding RNAs that tune immune cell responses to physiological perturbations and play roles in pathological conditions in macrophages. To determine if a microRNA played any role in Tet2 activity, we examined the interrelationship of Tet2 action and the let-7 microRNA family, utilizing several let-7 microRNA engineered murine models. We first showed that Tet2, but not Tet3, is a direct target of the let-7a-1/let-7d/let-7f-1 (let-7adf) microRNAs in macrophages. We found that overexpression or deletion of the let-7adf gene cluster causes altered IL-6 induction both in tissue culture cells induced by LPS treatment in vitro as well as in a Salmonella infection mouse model in vivo. Mechanistically, let-7adf promotes IL-6 by directly repressing Tet2 levels and indirectly by enhancing a Tet2 suppressor, the key TCA cycle metabolite, succinate. We found that Let-7adf promotes succinate accumulation by regulating the Lin28a/Sdha axis. We thereby identify two pathways of let-7 control of Tet2 and, in turn, of the key inflammatory cytokine, IL-6, thus characterizing a regulatory pathway in which a microRNA acts as a feedback inhibitor of inflammatory processes.

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Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Cited by 74 publications

References 50 publications

Plasma cells: You are what you eat

Plasma cells: You are what you eat

Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis

Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages

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