ARF: Connecting senescence and innate immunity for clearance

Kearney, Alper Y.; Anchang, Benedict; Plevritis, Sylvia K.; Felsher, Dean W.

doi:10.18632/aging.100813

Cited by 3 publications

(3 citation statements)

References 17 publications

(21 reference statements)

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“…Murakami et al [ 71 ] recently showed that p16(Ink4a) regulates degradation of IRAK1 and consequent secretion of IL-6 in mouse and human macrophages but not fibroblasts. In addition, another senescence-associated tumor suppressor p19ARF has been reported as a new p53-independent regulator of inflammatory response in macrophages modulating TLRs signaling [ 72 , 73 ]. Hence, the induction of the senescence-associated macrophage (SAM) phenotype may not specifically require SCs, but rather represent a specific type of macrophage activation or differentiation in response to certain natural physiological stimuli.…”

Section: Discussionmentioning

confidence: 99%

Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells

Hall

Balan

Gleiberman

et al. 2016

Aging

251

261

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Senescent cells (SCs) have been considered a source of age-related chronic sterile systemic inflammation and a target for anti-aging therapies. To understand mechanisms controlling the amount of SCs, we analyzed the phenomenon of rapid clearance of human senescent fibroblasts implanted into SCID mice, which can be overcome when SCs were embedded into alginate beads preventing them from immunocyte attack. To identify putative SC killers, we analyzed the content of cell populations in lavage and capsules formed around the SC-containing beads. One of the major cell types attracted by secretory factors of SCs was a subpopulation of macrophages characterized by p16(Ink4a) gene expression and β-galactosidase activity at pH6.0 (β-galpH6), thus resembling SCs. Consistently, mice with p16(Ink4a) promoter-driven luciferase, developed bright luminescence of their peritoneal cavity within two weeks following implantation of SCs embedded in alginate beads. p16(Ink4a)/β-galpH6-expressing cells had surface biomarkers of macrophages F4/80 and were sensitive to liposomal clodronate used for the selective killing of cells capable of phagocytosis. At the same time, clodronate failed to kill bona fide SCs generated in vitro by genotoxic stress. Old mice with elevated proportion of p16(Ink4a)/β-galpH6-positive cells in their tissues demonstrated reduction of both following systemic clodronate treatment, indicating that a significant proportion of cells previously considered to be SCs are actually a subclass of macrophages. These observations point at a significant role of p16(Ink4a)/β-galpH6-positive macrophages in aging, which previously was attributed solely to SCs. They require re-interpretation of the mechanisms underlying rejuvenating effects following eradication of p16(Ink4a)/β-galpH6-positive cells and reconsideration of potential cellular target for anti-aging treatment.

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Section: Discussionmentioning

confidence: 99%

Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells

Hall

Balan

Gleiberman

et al. 2016

Aging

251

261

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“…212 ARF is required for MYC to regulate the expression of genes involved in innate immune activation. 100 Interestingly, CD8 + T cells in Cdkn2a –/– mice have been shown to produce significantly lower amounts of IL-10 and thus are more susceptible to 2,4,6-trinitrobenzenesulfonic acid (TNBS)–induced colitis. 216…”

Section: Discussionmentioning

confidence: 99%

Globule Leukocytes and Other Mast Cells in the Mouse Intestine

et al. 2017

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Only 2 major mast cell (MC) subtypes are commonly recognized in the mouse: the large connective tissue mast cells (CTMCs) and the mucosal mast cells (MMCs). Interepithelial mucosal inflammatory cells, most commonly identified as globule leukocytes (GLs), represent a third MC subtype in mice, which we term interepithelial mucosal mast cells (ieMMCs). This term clearly distinguishes ieMMCs from lamina proprial MMCs (lpMMCs) while clearly communicating their common MC lineage. Both lpMMCs and ieMMCs are rare in normal mouse intestinal mucosa, but increased numbers of ieMMCs are seen as part of type 2 immune responses to intestinal helminth infections and in food allergies. Interestingly, we found that increased ieMMCs were consistently associated with decreased mucosal inflammation and damage, suggesting that they might have a role in controlling helminth-induced immunopathology. We also found that ieMMC hyperplasia can develop in the absence of helminth infections, for example, in Treg-deficient mice, Arf null mice, some nude mice, and certain graft-vs-host responses. Since tuft cell hyperplasia plays a critical role in type 2 immune responses to intestinal helminths, we looked for (but did not find) any direct relationship between ieMMC and tuft cell numbers in the intestinal mucosa. Much remains to be learned about the differing functions of ieMMCs and lpMMCs in the intestinal mucosa, but an essential step in deciphering their roles in mucosal immune responses will be to apply immunohistochemistry methods to consistently and accurately identify them in tissue sections.

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“…Chronic wounds and flare-ups are long-term complications after SM exposure and thus there needs to be some kind of “memory”, which may be senescent cells due to their longevity. Senescence is part of many cellular mechanisms including aging (Baker et al 2016 ), age-related diseases (Baker et al 2011 ), tissue remodeling (Krizhanovsky et al 2008 ), wound healing (Jun and Lau 2010 ) and immunity (Kearney et al 2015 ). Recently, senescence was defined as a specific permanent growth arrest of proliferation-competent cell induced by stressors (Sharpless and Sherr 2015 ) like reactive oxygen species (ROS) (von Zglinicki 2002 ) or unresolved DNA damage (Sedelnikova et al 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard

Rothmiller

Jäger²,

Meier³

et al. 2021

Arch Toxicol

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Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.

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ARF: Connecting senescence and innate immunity for clearance

Cited by 3 publications

References 17 publications

Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells

Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells

Globule Leukocytes and Other Mast Cells in the Mouse Intestine

Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard

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