The emerging role of microRNA in regulation of endotoxin tolerance

Quinn, Edel; Wang, Jianghuai; Redmond, H. P.

doi:10.1189/jlb.1111571

Cited by 60 publications

(67 citation statements)

References 72 publications

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“…Transfection of cells with an inhibitor and a mimic of miR-146a confirmed its role in tolerance induction. Our data acquired with neisserial LOS are in accord with those of other laboratories that have reported the critical role of miR-146a in endotoxin tolerance (43,44). Overall, it has been increasingly recognized that the suppression of immunity is a component of the response to Gramnegative bacterial septicemia that facilitates infection and leads to a subsequent systemic response and circulatory collapse that is the primary cause of death in industrialized countries.…”

Section: Table 4 Expression Of Pea (A) O-acetate (B) and Sialic Acisupporting

confidence: 80%

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage

John

Phillips²,

Din

et al. 2016

Journal of Biological Chemistry

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The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1-3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-␣ in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections.Our previous studies of neisserial lipooligosaccharide (LOS) 2 and the human innate immune system have shown that the degree of phosphorylation of the lipid A component is correlated with the potential of the LOS to induce inflammation stimulated by innate immunity as revealed by cytokine induction in human monocytes in vitro and, in general, with the severity of infections (1-3). In the LOS of Neisseria meningitidis, the modification of lipid A with phosphoethanolamine (PEA) also has been shown to inhibit the bactericidal activity of cathepsin G within neutrophil extracellular traps (4) and to increase adhesion of the bacteria to human cells (5). Expression of PEA on the oligosaccharide (OS) of meningococcal LOS (Fig. 1), particularly in the O-3 position on heptose (Hep) II, or expression of sialic acid (Neu5Ac) have been shown to inhibit activation of complement via the classical and alternative pathways (6 -9). In this study, we postulated that analysis of the structures of the LOS and the genomic diversity of genes for LOS biosynthesis would reveal differences associated with the severity of meningococcal infection and with carrier versus invasive strains of N. meningitidis.To ascertain whether such differences exist, we characterized the structures of LOS from isolates from infected patients or from carriers of N. meningitidi...

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Section: Table 4 Expression Of Pea (A) O-acetate (B) and Sialic Acisupporting

confidence: 80%

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage

John

Phillips²,

Din

et al. 2016

Journal of Biological Chemistry

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“…Evidence is now emerging indicating that miR might constitute an additional negative feedback mechanism operating in the innate immune system (22)(23)(24). MiR-146a has been the first miR associated to the inflammatory response, described as an miR rapidly induced by proinflammatory stimuli in phagocytes (15), and experimental evidence has clearly defined its role of negative regulator of inflammation (10,25,26) and its involvement in endotoxin tolerance (27,28). The miR-146 family also includes miR-146b, which is encoded by a distinct gene on a separate chromosome and only differs from miR-146a by 2 nt at the 3′ end in its mature sequence.…”

Section: Discussionmentioning

confidence: 99%

Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b

Curtale

Mirolo²,

Renzi

et al. 2013

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

245

234

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Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses that, subsequently, prime specific adaptive responses. Several mechanisms control TLR activity to avoid excessive inflammation and consequent immunopathology, including the anti-inflammatory cytokine IL-10. Recently, several TLR-responsive microRNAs (miRs) have also been proposed as potential regulators of this signaling pathway, but their functional role during the inflammatory response still is incompletely understood. In this study, we report that, after LPS engagement, monocytes up-regulate miR-146b via an IL-10–mediated STAT3-dependent loop. We show evidence that miR-146b modulates the TLR4 signaling pathway by direct targeting of multiple elements, including the LPS receptor TLR4 and the key adaptor/signaling proteins myeloid differentiation primary response (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6). Furthermore, we demonstrate that the enforced expression of miR-146b in human monocytes led to a significant reduction in the LPS-dependent production of several proinflammatory cytokines and chemokines, including IL-6, TNF-α, IL-8, CCL3, CCL2, CCL7, and CXCL10. Our results thus identify miR-146b as an IL-10–responsive miR with an anti-inflammatory activity based on multiple targeting of components of the TLR4 pathway in monocytes and candidate miR-146b as a molecular effector of the IL-10 anti-inflammatory activity.

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“…15,26 Lastly, miR-125b regulates adaptation of cell metabolism to cancer transformation 27 and is one of the master miRNAs involved in the Toll-like receptor 4 (TLR4) signaling pathway during the development of endotoxin tolerance. 25,28 To provide novel insight into the integrated genetic regulatory network specifying cell fate, we have searched for novel target genes of miR-125b and further explored its role in the context of human monocytes, including the mechanisms on mitochondria metabolism.…”

Section: Introductionmentioning

confidence: 99%

miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

Duroux-Richard

Roubert

Ammari

et al. 2016

Blood

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Key Points• miR-125b reduces mitochondrial respiration and promotes elongation of mitochondrial network through BIK and MTP18 silencing, respectively. • The miR-125b/BIK/MTP18 axis promotes adaptation of monocytes to inflammation.Metabolic changes drive monocyte differentiation and fate. Although abnormal mitochondria metabolism and innate immune responses participate in the pathogenesis of many inflammatory disorders, molecular events regulating mitochondrial activity to control life and death in monocytes remain poorly understood. We show here that, in human monocytes, microRNA-125b (miR-125b) attenuates the mitochondrial respiration through the silencing of the BH3-only proapoptotic protein BIK and promotes the elongation of the mitochondrial network through the targeting of the mitochondrial fission process 1 protein MTP18, leading to apoptosis. Proinflammatory activation of monocyte-derived macrophages is associated with a concomitant increase in miR-125b expression and decrease in BIK and MTP18 expression, which lead to reduced oxidative phosphorylation and enhanced mitochondrial fusion. In a chronic inflammatory systemic disorder, CD14 1 blood monocytes display reduced miR-125b expression as compared with healthy controls, inversely correlated with BIK and MTP18 messenger RNA expression. Our findings not only identify BIK and MTP18 as novel targets for miR-125b that control mitochondrial metabolism and dynamics, respectively, but also reveal a novel function for miR-125b in regulating metabolic adaptation of monocytes to inflammation. Together, these data unravel new molecular mechanisms for a proapoptotic role of miR-125b in monocytes and identify potential targets for interfering with excessive inflammatory activation of monocytes in inflammatory disorders. (Blood. 2016;128(26): 3125-3136)

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The emerging role of microRNA in regulation of endotoxin tolerance

Cited by 60 publications

References 72 publications

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage

Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b

miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

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