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The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence.

ABSTRACT: Human primary monocytes comprise a heterogeneous population that can be classified into three subsets based on CD14 and CD16 expression: classical (CD14high/CD16-), intermediate (CD14high/CD16+), and non-classical (CD14low/CD16+). The non-classical monocytes are the most pro-inflammatory in response to TLR stimulation in vitro, yet they express a remarkably high basal level of miR-146a, a microRNA known to negatively regulate the TLR pathway. This concurrence of a pro-inflammatory status and a high miR-146a level has been associated with cellular senescence in other cell types. Hence, we assessed the three monocyte subsets for evidence of senescence, including proliferative status, telomere length, cellular ROS levels, and mitochondrial membrane potential. Indeed, the non-classical subset exhibited the clearest hallmarks of senescence, followed by the intermediate and then the classical subset. In addition, the non-classical subset secreted pro-inflammatory cytokines basally in vitro. The highly pro-inflammatory nature of the non-classical monocytes could be a manifestation of the senescence-associated secretory phenotype (SASP), likely induced by a high basal NF-?B activity and IL-1? production. Finally, we observed an accumulation of the non-classical monocytes, in conjunction with higher levels of plasma TNF-? and IL-8, in the elderly. These factors may contribute to inflamm-aging and age-related inflammatory conditions, such as atherosclerosis and osteoarthritis. With our new understanding that the non-classical monocyte subset is a senescent population, we can now re-examine the role of this subset in disease conditions where this subset expands.

SUBMITTER: Ong SM

PROVIDER: S-EPMC5833376 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence.

Ong Siew-Min SM Hadadi Eva E Dang Truong-Minh TM Yeap Wei-Hseun WH Tan Crystal Tze-Ying CT Ng Tze-Pin TP Larbi Anis A Wong Siew-Cheng SC

Cell death & disease 20180215 3

Human primary monocytes comprise a heterogeneous population that can be classified into three subsets based on CD14 and CD16 expression: classical (CD14high/CD16-), intermediate (CD14high/CD16+), and non-classical (CD14low/CD16+). The non-classical monocytes are the most pro-inflammatory in response to TLR stimulation in vitro, yet they express a remarkably high basal level of miR-146a, a microRNA known to negatively regulate the ...[more]

PMID: 29449647

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Project description:Acute myocardial infarction (AMI) evokes a temporally coordinated immune response, in which monocytes are critically involved in the clearance of cell debris; however, excessive inflammation induced by the classical sub-population of monocytes frequently limits the endogenous reparative process. In the present study, the potential of the anti-inflammatory adipokine complement C1q tumor necrosis factor (TNF)-related protein-3 (CTRP3) to induce intermediate switch of monocytes to an anti-inflammatory phenotype was explored. Circulating monocytes were isolated from patients with AMI at various time-points (3-5 h, 3 days and 7 days) and categorized by flow cytometry/immunostaining into three sub-divisions based on the expression of CD14 and CD16 epitopes: Classical (CD14++/CD16-), non-classical (CD14+/CD16++) and intermediate populations (CD14++/CD16+). The phagocytic activity was evaluated by the ingestion of FITC-Zymosan and 19F-nanoemulsion and the migratory activity using Thin Cert™ Transwell assay. Monocytes were cultured using autologous serum in the presence of CTRP3 (1 µg/ml) for 24 h and the expression of interleukin 6 (IL-6) and TNF-α was quantified by reverse-transcription quantitative PCR. In addition, SB203580, a p38 mitogen-activated protein kinase (MAPK)/ERK inhibitor, was used to examine the downstream pathways of CTRP3. AMI evoked a transient increase in monocyte counts of the classical subset after onset of the ischemic insult, while the non-classical and intermediate subsets persistently expanded (P<0.01). The monocytes from patients at 3 days after AMI displayed enhanced phagocytic and migratory activities in comparison with those from healthy volunteers (P<0.01). Of note, addition of CTRP3 induced an intermediate switch of monocyte subsets and antagonized the enhanced expression of cytokines, particularly IL-6, in monocytes stressed by lipopolysaccharides, likely by blunting the ERK1/2 and P38 MAPK signaling pathway. In conclusion, the present study demonstrated a dynamic fluctuation of monocyte subsets and enhanced phagocytic and migratory activities in patients with AMI. Furthermore, the 'proof-of-concept' evidence pinpoints CTRP3 as an alternative candidate to modulate the 'uncontrolled' inflammatory response and thus to augment cardiac reparative processes in patients with AMI.

Dataset Information

The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence.

Publications

The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence.

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