miRNA in Macrophage Development and Function

Abstract

Significance: MicroRNAs (miRNAs) control cellular gene expression via primarily binding to 3¢ or 5¢ untranslated region of the target transcript leading to translational repression or mRNA degradation. In most cases, miRNAs have been observed to fine-tune the cellular responses and, therefore, act as a rheostat rather than an on/off switch. Transcription factor PU.1 is a master switch that controls monocyte/macrophage development from hematopoietic stem cells. Recent Advances: PU.1 induces a specific set of miRNAs while suppressing the miR17-92 cluster to regulate monocyte/macrophage development. In addition to development, miRNAs tightly control the macrophage polarization continuum from proinflammatory M1 or proreparative M2 by regulating expression of key transcription factors involved in the process of polarization. Critical Issues: miRNAs are intricately involved with fine-tuning fundamental macrophage functions such as phagocytosis, efferocytosis, inflammation, tissue repair, and tumor promotion. Macrophages are secretory cells that participate in intercellular communication by releasing regulatory molecules and microvesicles (MVs). MVs are bilayered lipid membranes packaging a hydrophilic cargo, including proteins and nucleic acids. Macrophage-derived MVs carry functionally active miRNAs that suppress gene expression in target cells via post-transcriptional gene silencing, thus regulating cell function. In summary, miRNAs fine-tune several major facets of macrophage development and function. Such fine-tuning is critical in preventing exaggerated macrophage response to endogenous or exogenous stimuli. Future Directions: A critical role of miRNAs in the regulation of innate immune response and macrophage biology, including development, differentiation, and activation, has emerged. A clear understanding of such regulation on macrophage function remains to be elucidated. Antioxid. Redox Signal. 25, 795-804.

Long non‐coding RNA expressed in macrophage co‐varies with the inflammatory phenotype during macrophage development and polarization

“…This complex differentiation process requires a coordinated expression of transcription factors, cytokines and ncRNAs . Although many of well‐defined miRNAs have been recognized as key regulators involved in haematopoietic differentiation, there were few reports about lncRNAs regulating monocyte/macrophage differentiation . Chen et al have revealed that phorbol‐12‐myristate‐13‐acetate (PMA) could raise the long non‐coding monocytic RNA (lnc‐MC) expression in human THP‐1 cell line, HL‐60 cell line and CD34+ haematopoietic stem‐progenitor cells (HSPCs).…”

“…That macrophage might be polarized through the JNK pathway after binding to CCR2 and nuclear factor‐κB (NF‐κB), or through the activation of PI3K with increased RelA/NF‐κB activity . Functionally, M1‐type macrophage promotes Th1 response and produces copious amounts of pro‐inflammatory cytokines or reactive oxygen species (ROS) to kill pathogens . TLR‐triggered NF‐κB is one of the best studied pathways participated in the conversion of macrophage to M1‐like phenotype, which is shown in Figure .…”

“…Macrophage activated through an opposite manner is known as M2 type. M2 macrophage plays an essential role in adaptive response and contributes to Th2‐type response involved in acute tissue damage and repair . However, studies on the expression of lncRNAs in M2 macrophage are still rare, and the exact mechanism of action is still unclear.…”

“…43 Although many of well-defined miRNAs have been recognized as key regulators involved in haematopoietic differentiation, there were few reports about lncR-NAs regulating monocyte/macrophage differentiation. 44 Chen et al have revealed that phorbol-12-myristate-13-acetate (PMA) could raise the long non-coding monocytic RNA (lnc-MC) expression in human THP-1 cell line, HL-60 cell line and CD34+ haematopoietic stem-progenitor cells (HSPCs). Mechanically, lnc-MC acted as a ceRNA to soak up miR-199a-5p and release activin A receptor type 1B (ACVR1B), 45 then enhanced the effect of haematopoiesis-specific transcription factor PU.1 on suppressing miR-199a-5p and eventually facilitated the differentiation process through activating the transforming growth factor β (TGF-β).…”

“…8 Functionally, M1-type macrophage promotes Th1 response and produces copious amounts of pro-inflammatory cytokines or reactive oxygen species (ROS) to kill pathogens. 44 TLR-triggered NF-κB is one of the best studied pathways participated in the conversion of macrophage to M1-like phenotype, 49 which is shown in Figure 3. [50][51][52][53] All TLRs, excluding TLR3, mainly activate the NF-κB-dependent or IRF7-dependent type I IFN (TLR7-9) pro-inflammatory signallings via the adapter protein myeloid differentiation marker 88 (MyD88).…”