Age-related changes in tissue macrophages precede cardiac functional impairment

Pinto, Alexander R.; Godwin, James; Chandran, Anjana; Hersey, Lucy; Ilinykh, Alexei; Debuque, Ryan; Wang, Lina; Rosenthal, Nadia

doi:10.18632/aging.100669

Cited by 85 publications

(99 citation statements)

References 37 publications

(45 reference statements)

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“…4B-4C). These findings are also consistent with the reported observations that show downregulation of immune response genes (45). Interestingly, we found a lesser number of neutrophils in TLR2-KO hearts (Fig.…”

Section: Tlr2 Deficient Hearts Harbour Reduced Residual Macrophages Asupporting

confidence: 94%

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Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Spurthi

Sarikhani

Mishra

et al. 2018

Journal of Biological Chemistry

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Toll-like receptors (TLRs) are a family of patternrecognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied agingassociated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8-and 12-months-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-monthsold TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophyrelated ubiquitin ligases MuRF-1 and Atrogin-1. Mechanistically, TLR2-deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor forkhead box protein O1 (FoxO1), and, in turn, to elevated expression of FoxO target genes involved in regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling, while improving the contractile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice.

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Section: Tlr2 Deficient Hearts Harbour Reduced Residual Macrophages Asupporting

confidence: 94%

“…Age-dependent decline in the number of macrophages has been observed in aging hearts (35,43). Therefore, we tested whether TLR2-KO hearts showed any changes in the population of macrophages in the heart.…”

Section: Tlr2 Deficient Hearts Harbour Reduced Residual Macrophages Amentioning

confidence: 99%

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Spurthi

Sarikhani

Mishra

et al. 2018

Journal of Biological Chemistry

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“…In the heart, we and others have recently shown that cTMs are also proliferative (Fig. 2), dividing throughout life (Epelman et al, 2014;Heidt et al, 2014;Pinto et al, 2014).…”

Section: Embryonic and Adult Origins Of Cardiac Tissue Macrophagesmentioning

confidence: 67%

Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation

2014

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Macrophages are an immune cell type found in every organ of the body. Classically, macrophages are recognised as housekeeping cells involved in the detection of foreign antigens and danger signatures, and the clearance of tissue debris. However, macrophages are increasingly recognised as a highly versatile cell type with a diverse range of functions that are important for tissue homeostasis and injury responses. Recent research findings suggest that macrophages contribute to tissue regeneration and may play a role in the activation and mobilisation of stem cells. This review describes recent advances in our understanding of the role played by macrophages in cardiac tissue maintenance and repair following injury. We examine the involvement of exogenous and resident tissue macrophages in cardiac inflammatory responses and their potential activity in regulating cardiac regeneration.

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“…Such monocyte-derived cardiac macrophages have been reported to hold higher proinflammatory potential, compared with their embryonic counterparts (5). Furthermore, Pinto et al (57) reported that a profibrotic resident macrophage subset (defined as CX3CR1 low CD206 + ) arises in the myocardium of 30-wk-old animals. In the current study, we also expand these observations and report shifts in the myocardial myeloid compartment at advanced ages (in animals aged 12 to 15 mo old).…”

Section: Discussionmentioning

confidence: 99%

Myocardial aging as a T-cell–mediated phenomenon

Ramos

Berg²,

Silva

et al. 2017

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

142

117

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In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissueresident leukocytes and with an accumulation of activated CD4 + Foxp3 − (forkhead box P3) IFN-γ + T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.T he myocardial cellular composition has been revisited in recent years, and leukocyte subsets residing in the healthy heart have been described (1-10). Cardiac-resident macrophages exhibiting an M2-like gene expression profile were found to be distributed in close association with the coronary vascular bed (3), and niches for dendritic cells (CD11c + MHC-II high CD80/86 low ) were found near the cardiac valves of the intact heart (1). It was also demonstrated that cardiac-resident MHCII + cells process and present myosin heavy chain-alpha-derived peptides under steady-state conditions (11, 12) and prime T cells ex vivo (1). However, whether lymphocytes can seed the intact myocardium and whether T-cell priming with myocardial antigens can occur in the absence of an infection or autoimmune myocarditis remain elusive.More recently, accumulating evidence indicated that noninfectious myocardial diseases are modulated by T cells. During the last couple of years, our group demonstrated that ischemic, sterile myocardial injuries can elicit lymphocyte activation directed against cardiac antigens (13-16). Our previous data, showing for the first time that CD4 + T cells reactive to cardiac components can foster the healing process that takes place after myocardial infarction, were corroborated by several other reports (13,15,(17)(18)(19)(20). However, these autoreactive T cells can also b...

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Age-related changes in tissue macrophages precede cardiac functional impairment

Cited by 85 publications

References 37 publications

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation

Myocardial aging as a T-cell–mediated phenomenon

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