CCL24
C-C motif chemokine 24 precursor (CK-beta-6) (Eosinophil chemotactic protein 2) (Eotaxin-2) (Myeloid progenitor inhibitory factor 2) (MPIF-2) (Small-inducible cytokine A24) [MPIF2] [SCYA24]
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The neonatal mouse heart is capable of transiently regenerating after injury from postnatal day (P) 0-7 and macrophages are found important in this process. However, whether macrophages alone are sufficient to orchestrate this regeneration; what regulates cardiomyocyte proliferation; why cardiomyocytes do not proliferate after P7; and whether adaptive immune cells such as regulatory T-cells (Treg) influence neonatal heart regeneration have less studied. : We employed both loss- and gain-of-function transgenic mouse models to study the role of Treg in neonatal heart regeneration. In loss-of-function studies, we treated mice with the lytic anti-CD25 antibody that specifically depletes Treg; or we treated FOXP3 with diphtheria toxin that specifically ablates Treg. In gain-of-function studies, we adoptively transferred hCD2 Treg from NOD.[i]Foxp3[/i] to NOD/SCID that contain Treg as the only T-cell population. Furthermore, we performed single-cell RNA-sequencing of Treg to uncover paracrine factors essential for cardiomyocyte proliferation. : Unlike their wild type counterparts, NOD/SCID mice that are deficient in T-cells but harbor macrophages fail to regenerate their injured myocardium at as early as P3. During the first week of injury, Treg are recruited to the injured cardiac muscle but their depletion contributes to more severe cardiac fibrosis. On the other hand, adoptive transfer of Treg results in mitigated fibrosis and enhanced proliferation and function of the injured cardiac muscle. Mechanistically, single-cell transcriptomic profiling reveals that Treg could be a source of regenerative factors. Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner; and their secreted factors such as CCL24, GAS6 or AREG potentiate neonatal cardiomyocyte proliferation. By comparing the regenerating P3 and non-regenerating P8 heart, there is a significant increase in the absolute number of intracardiac Treg but the whole transcriptomes of these Treg do not differ regardless of whether the neonatal heart regenerates. Furthermore, even adult Treg, given sufficient quantity, possess the same regenerative capability. : Our results demonstrate a regenerative role of Treg in neonatal heart regeneration. Treg can directly facilitate cardiomyocyte proliferation in a paracrine manner.
MeSH Terms
- Adoptive Transfer
- Aging
- Animals
- Animals, Newborn
- Cell Proliferation
- Fibrosis
- Forkhead Transcription Factors
- Gene Expression Regulation, Developmental
- Heart
- Humans
- Immunity, Innate
- Loss of Function Mutation
- Macrophages
- Mice, Inbred NOD
- Mice, SCID
- Myocardial Infarction
- Myocytes, Cardiac
- Paracrine Communication
- Regeneration
- T-Lymphocytes, Regulatory
- Transcriptome
- Up-Regulation
Keywords
- CD4 regulatory T-cells
- cardiac fibrosis
- cardiomyocyte proliferation
- heart regeneration
- macrophages
- single-cell RNA-seq
Our goal was to determine whether anserine/carnosine supplementation (ACS) suppresses chemokine levels in elderly people. In a double-blind randomized controlled trial, volunteers were assigned to the ACS or placebo group (1:1). Sixty healthy elderly volunteers (active, [i]n[/i] = 30; placebo, [i]n[/i] = 30) completed the study. The ACS group was administered 1.0 g of anserine/carnosine (3:1) for 3 months. A microarray analysis and subsequent quantitative real-time polymerase chain reaction (qRT-PCR) analysis of peripheral blood mononuclear cells (PBMCs) showed decreased expression of CCL24, an inflammatory chemokine ([i]p[/i] < 0.05). Verbal memory, assessed using the Wechsler memory scale-logical memory, was preserved in the ACS group. An age-restricted sub-analysis showed significant verbal memory preservation by ACS in participants who were in their 60s (active, [i]n[/i] = 12; placebo, [i]n[/i] = 9; [i]p[/i] = 0.048) and 70s (active, [i]n[/i] = 7; placebo, [i]n[/i] = 11; [i]p[/i] = 0.017). The suppression of CCL24 expression was greatest in people who were in their 70s ([i]p[/i] < 0.01). There was a significant correlation between the preservation of verbal memory and suppression of CCL24 expression in the group that was in the 70s (Poisson correlation, [i]r[/i] = 0.46, [i]p[/i] < 0.05). These results suggest that ACS may preserve verbal episodic memory, probably owing to CCL24 suppression in the blood, especially in elderly participants.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Anserine
- Biomarkers
- Carnosine
- Chemokine CCL24
- Cognition
- Dietary Supplements
- Double-Blind Method
- Down-Regulation
- Drug Combinations
- Female
- Humans
- Inflammation Mediators
- Leukocytes, Mononuclear
- Male
- Memory Disorders
- Memory, Episodic
- Middle Aged
- Time Factors
- Tokyo
- Treatment Outcome
Keywords
- Alzheimer’s disease
- CCL24
- RCT
- anserine and carnosine
- cognitive function
- elderly people
- inflammatory chemokine
- verbal memory