G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence

Sun, Shuning; Ni, Shi-Hao; Li, Yue; Liu, Xin; Deng, Jianping; Chen, Zixin; Li, Huan; Feng, Wenjun; Huang, Yu‐Sheng; Li, Da-Nian; Xian, Shaoxiang; Yang, Zhong-Qi; Wang, Lingjun; Lu, Lu

doi:10.1038/s41419-021-03874-7

Cited by 40 publications

(24 citation statements)

References 48 publications

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“…It has been shown that S100A8 could induce cellular senescence-like changes in bovine oviduct epithelial cells (Nakamura et al 2019). Similarly, S100A8/A9 promoted aging-related cardiac fibrosis in myeloid-derived suppressor cells (Sun et al 2021). At the organ level, in lungs, for example, aging per se was followed by CS and concomitant upregulation of S100A8 and increased severity of lung inflammation (Rashid et al 2018).…”

Section: Discussionmentioning

confidence: 99%

TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging

et al. 2022

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TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9–/– mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9–/– animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators ( Il-6, Rankl, Cxcl8) and danger signals ( S100A8, S100A9) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9–/– mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16 INK4a/p19 ARF ratio compared to the younger groups and aged TLR9–/– animals. Ex vivo experiments with bone marrow–derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population.

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Section: Discussionmentioning

confidence: 99%

TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging

et al. 2022

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“…Fibronectin-EDA and TLR2/4 were matched in cardiac fibrosis, causing myofibroblasts to begin producing collagen I and III ( 30 ). Following the combination of S100A8/A9 and TLR4, which was intended to produce cardiac fibrosis, the expression of α-SMA, collagen 1A1, and 3A1 mRNA was also enhanced in fibroblasts ( 31 , 32 ).In pulmonary fibrosis, HSP90 and uric acid react with TLR2/4, aggravating the expression of TIMP-1 and the synthesis of fibronectin ( 33 ). S100A4 is also associated with TLR4 leading to elevated α-SMA expression and increased collagen I synthesis during pulmonary fibrosis ( 34 ).…”

Section: Introductionmentioning

confidence: 99%

Examination of the role of necroptotic damage-associated molecular patterns in tissue fibrosis

Liu

Chen

2022

Front. Immunol.

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Fibrosis is defined as the abnormal and excessive deposition of extracellular matrix (ECM) components, which leads to tissue or organ dysfunction and failure. However, the pathological mechanisms underlying fibrosis remain unclear. The inflammatory response induced by tissue injury is closely associated with tissue fibrosis. Recently, an increasing number of studies have linked necroptosis to inflammation and fibrosis. Necroptosis is a type of preprogrammed death caused by death receptors, interferons, Toll-like receptors, intracellular RNA and DNA sensors, and other mediators. These activate receptor-interacting protein kinase (RIPK) 1, which recruits and phosphorylates RIPK3. RIPK3 then phosphorylates a mixed lineage kinase domain-like protein and causes its oligomerization, leading to rapid plasma membrane permeabilization, the release of cellular contents, and exposure of damage-associated molecular patterns (DAMPs). DAMPs, as inflammatory mediators, are involved in the loss of balance between extensive inflammation and tissue regeneration, leading to remodeling, the hallmark of fibrosis. In this review, we discuss the role of necroptotic DAMPs in tissue fibrosis and highlight the inflammatory responses induced by DAMPs in tissue ECM remodeling. By summarizing the existing literature on this topic, we underscore the gaps in the current research, providing a framework for future investigations into the relationship among necroptosis, DAMPs, and fibrosis, as well as a reference for later transformation into clinical treatment.

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“… 28 , 29 Furthermore, the profibrotic function of MDSCs have already been described in different organs and conditions. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

“…Even more interestingly, MDSCs may stimulate fibrosis either by secreting pro‐fibrotic mediators (IL6, TGF‐β, VEGF e PDGF), by differentiating in collagen‐producing fibrocytes, or by releasing proline (a major component of collagen and catabolite of Arginase‐1‐mediated reactions) 28,29 . Furthermore, the profibrotic function of MDSCs have already been described in different organs and conditions 30,31 …”

Section: Discussionmentioning

confidence: 99%

Arginase‐1+ bone marrow myeloid cells are reduced in myeloproliferative neoplasms and correlate with clinical phenotype, fibrosis, and molecular driver

et al. 2022

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Introduction: Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal myeloid proliferative disorders characterized by sustained systemic inflammation. Despite its renowned importance, the knowledge concerning the inflammatory pathophysiology of these conditions is currently limited to studies on serum cytokines, while cellular immunity has rarely been investigated. How to cite this article:Bonometti A, Borsani O, Rumi E, et al. Arginase-1+ bone marrow myeloid cells are reduced in myeloproliferative neoplasms and correlate with clinical phenotype, fibrosis, and molecular driver.

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G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence

Cited by 40 publications

References 48 publications

TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging

TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging

Examination of the role of necroptotic damage-associated molecular patterns in tissue fibrosis

Arginase‐1+ bone marrow myeloid cells are reduced in myeloproliferative neoplasms and correlate with clinical phenotype, fibrosis, and molecular driver

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