Post-transcriptional regulation of gene expression in innate immunity

Carpenter, Susan; Ricci, Emiliano P.; Mercier, Blandine C.; Moore, Melissa J.; Fitzgerald, Katherine A.

doi:10.1038/nri3682

Cited by 322 publications

(275 citation statements)

References 137 publications

Supporting

Mentioning

268

Contrasting

Order By: Relevance

“…Nevertheless, the brake of Bcl6/Dusp1 can be effectively removed by the induction of miR-127 upon the sustained stimulation, and thereby initiates the inflammatory response. Thus, it appears that, by fine-tuning the Bcl6/Dusp1/JNK cascade, miR-127 calibrates the activation signaling for macrophages to prevent an energycostly response under short-term stress while maintaining the dynamic responsiveness when necessary (38). Additionally, we noted that there occurred a slight decrease in miR-127 production at the late stage of the TLR response.…”

Section: Discussionmentioning

confidence: 74%

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

Ying

Kang

Zhang

et al. 2015

The Journal of Immunology

185

122

View full text Add to dashboard Cite

A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127–mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti–miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases.

show abstract

Section: Discussionmentioning

confidence: 74%

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

Ying

Kang

Zhang

et al. 2015

The Journal of Immunology

185

122

View full text Add to dashboard Cite

show abstract

“…The control of mRNA translation is emerging as a major mechanism that regulates the levels of proteins within leukocytes (reviewed in refs. 23,24). We have now identified a previously unidentified mechanism in which the most abundant neutrophil α-defensin, HNP1, which is readily released as these cells die (5), inhibits bulk protein translation within macrophages.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

Brook

Tomlinson

Miles

et al. 2016

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

View full text Add to dashboard Cite

Neutrophils are the first and most numerous cells to arrive at the site of an inflammatory insult and are among the first to die. We previously reported that alpha defensins, released from apoptotic human neutrophils, augmented the antimicrobial capacity of macrophages while also inhibiting the biosynthesis of proinflammatory cytokines. In vivo, alpha defensin administration protected mice from inflammation, induced by thioglychollate-induced peritonitis or following infection with Salmonella enterica serovar Typhimurium. We have now dissected the antiinflammatory mechanism of action of the most abundant neutrophil alpha defensin, Human Neutrophil Peptide 1 (HNP1). Herein we show that HNP1 enters macrophages and inhibits protein translation without inducing the unfolded-protein response or affecting mRNA stability. In a cell-free in vitro translation system, HNP1 powerfully inhibited both cap-dependent and cap-independent mRNA translation while maintaining mRNA polysomal association. This is, to our knowledge, the first demonstration of a peptide released from one cell type (neutrophils) directly regulating mRNA translation in another (macrophages). By preventing protein translation, HNP1 functions as a “molecular brake” on macrophage-driven inflammation, ensuring both pathogen clearance and the resolution of inflammation with minimal bystander tissue damage.

show abstract

“…Ligation of innate immune receptors triggers stereotypical cellular responses such as activation of NF-kB and MAPK signaling culminating in the expression of genes that shape the host response to infection, including inflammatory cytokines (5). Besides mRNA expression, key regulatory checkpoints of macrophage cytokine responses include posttranscriptional mRNA stabilization by p38 MAP-mediated MK2 activation and microRNAs (6). Posttrancriptional regulation of Mycobacterium tuberculosisinduced TNF production downstream of TLRs has been suggested (7) and microRNAs 125b and 155 have been implicated in the fine-tuning of macrophage TNF production induced by lipomannans of different mycobacterial species (8).…”

mentioning

confidence: 99%

RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection

Micaroni

Puyskens

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105−/− macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105−/− macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105−/− macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA–mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105−/− macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105−/− macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton’s tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.

show abstract

Post-transcriptional regulation of gene expression in innate immunity

Cited by 322 publications

References 137 publications

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection

Contact Info

Product

Resources

About