Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation

Abstract

Chronic inflammation is a major cause of disease. Inflammation resolution is in part directed by the differential stability of mRNAs encoding pro-inflammatory and anti-inflammatory factors. In particular, tristetraprolin (TTP)-directed mRNA deadenylation destabilizes AU-rich element (ARE)-containing mRNAs. However, this mechanism alone cannot explain the variety of mRNA expression kinetics that are required to uncouple degradation of pro-inflammatory mRNAs from the sustained expression of anti-inflammatory mRNAs. Here we show that the RNA-binding protein CPEB4 acts in an opposing manner to TTP in macrophages: it helps to stabilize anti-inflammatory transcripts harboring cytoplasmic polyadenylation elements (CPEs) and AREs in their 3′-UTRs, and it is required for the resolution of the LPS-triggered inflammatory response. Coordination of CPEB4 and TTP activities is sequentially regulated through MAPK signaling. Accordingly, CPEB4 depletion in macrophages impairs inflammation resolution in an LPS-induced sepsis model. We propose that the counterbalancing actions of CPEB4 and TTP, as well as the distribution of CPEs and AREs in their target mRNAs, define transcript-specific decay patterns required for inflammation resolution. Thus, these two opposing mechanisms provide a fine-tuning control of inflammatory transcript destabilization while maintaining the expression of the negative feedback loops required for efficient inflammation resolution; disruption of this balance can lead to disease.

Control of immediate early gene expression by CPEB4-repressor complex-mediated mRNA degradation

“…Apart from the regulation of CPEB activity through phosphorylation, the distance between the CPE and the poly(A) site was shown to be part of a combinatorial code that determines whether specific mRNAs are translationally activated (polyadenylated) or repressed (deadenylated) during meiotic progression of Xenopus oocytes [100]. Moreover, CPEB4 was recently found to stabilize CPE-and ARE-containing cytokine mRNAs in macrophages [101], indicating that cell-type-dependent differences may affect the function of CPEB4 within post-transcriptional regulatory complexes controlling the stability of selected mRNA subsets. In the future, it will be interesting to determine more precisely the molecular events that allow switching between the polyadenylation-promoting CPEB4activator complex and the CPEB4-repressor complex associated with CCR4-NOT-mediated mRNA deadenylation.…”

An intrinsically interpretable neural network architecture for sequence to function learning

“…Spi1/PU.1) for myeloid cells and Rorc and Eomes for innate lymphoid cells. These TFs are likewise well-characterized master regulators of their respective lineages (Suñer et al ., 2022; Hoorweg et al ., 2012; Kiekens et al ., 2021). Importantly, these TFs were also highlighted in the original analysis, and overall the and TF by cell-type matrices are highly similar; an important difference, though, is that for the model these are simply model parameters and no additional post-hoc calculations were required.…”

Resolvin D1 attenuated liver injury caused by chronic ethanol and acute LPS challenge in mice

“…Macrophage identity was confirmed by flow cytometry (>95% were F4/80 + CD11b + , data not shown). BMDMs were then treated for 2 h with 40 mM EtOH 32 ± 10 ng/ml LPS 33,34 with or without 10 nM RvD1 35 . The concentrations used in this study are based on previously reported experimental conditions to elicit biological responses in macrophages.…”