IL-6 can singlehandedly drive many features of frailty in mice

Jergović, Mladen; Thompson, Heather L.; Bradshaw, Christine M.; Sonar, Sandip Ashok; Ashgar, A.; Mohty, Niels; Joseph, Bellal; Fain, Mindy J.; Cleveland, Kristan H.; Schnellman, Rick G.; Nikolich‐Žugich, Janko

doi:10.1007/s11357-021-00343-z

Cited by 16 publications

(9 citation statements)

References 34 publications

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“…This is suggestive of a more youthful phenotype given that increased IL-6 in aging has long been associated with a decline in physical function, heightened inflammation, senescence, and mortality [ 7 , 59 – 61 ]. While IL-6 is but one cytokine, its importance was highlighted in a recent report showing that IL-6 can single-handedly drive features of frailty in mice [ 62 ]. The cellular source of IL-6 has also been shown to affect phenotype and downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

et al. 2022

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Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

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Section: Discussionmentioning

confidence: 99%

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

et al. 2022

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“…How to cope with aging, which causes systemic as well as topical frailty, is a growing subject of interest because of the aging society. Previous studies have reported strong association between inflammation and aging [14–16], which is the basis of the concept of inflammaging [17]. In inflammaging, which is clinically characterized by low-grade, chronic, and asymptomatic inflammation [18, 19], SASP factors such as IL-1, IL-6, IL-8, and TNF-α play a pivotal role in the progression of aging.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Aging becomes a serious issue in an aging society. Previous studies have reported that aging is strongly associated with inflammation [14][15][16], which is the basis of the concept of inflammaging [17]. Clinically, inflammaging consists of low-grade, chronic, and asymptomatic inflammation, characterized by increased blood levels of several inflammatory biomarkers, including IL-1, IL-6, IL-8, IL-18, and tumor necrosis factor-alpha (TNF-alpha), which are together called senescence-associated secretory phenotype (SASP) factors [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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IL-27 skews TNF-alpha-induced inflammatory microenvironment in keratinocytes

Aioi¹,

Imamichi

2022

Preprint

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Inflammaging has received considerable attention because aging is characterized by low-grade, chronic and asymptomatic inflammation, concomitant with increased blood levels of senescence-associated secretory phenotype (SASP) factors, including IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-alpha (TNF-alpha). On the other hand, IL-27 is not categorized as SASP factors though it is known that IL-27 has pleiotropic roles in inflammation. Here, we evaluated the interaction between TNF-alpha and IL-27 in the context of low-grade inflammation by using in HaCaT cells. TNF-alpha induced significant upregulation of IL-6 and IL-8 through the experimental concentrations (~10 ng/ml) of TNF-alpha while the mRNA expression levels of IL-1RA, IL-10 and IL-18BP were unchanged. After confirming the expression of IL-27 receptor in HaCaT cells, we examined the effects of IL-27 alone on the cytokine expression. IL-27 alone significantly enhanced mRNA expression levels of IL-10 and IL-18BP by 1.61-fold and 1.46-fold, respectively, and also enhanced mRNA expression levels of IL-6 by 2.32-fold. In the presence of 100 ng/ml IL-27, the expression levels of anti-inflammatory cytokines, IL-1RA, IL-10 and IL-18BP, were significantly upregulated with the treatment of a physiological concentration (1 ng/ml) TNF-alpha. Taken together, a high concentration of IL-27 exhibits anti-inflammatory effects in the presence of a low concentration of TNF-alpha when keratinocytes are the recipient of IL-27 signaling, suggesting the anti-inflammatory roles of IL-27 in inflammaging may be regulated by TNF-alpha concentration.

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“…Given the collective evidence supporting a regulatory interaction between c-Maf and CD153, we next determined factors that promote expression of c-Maf and whether c-Maf regulates CD153 expression in Tfh and Tfh10. As we (39) and others (40,41) have shown increased systemic IL-6 levels in aged mice, and IL-6 is known to induce c-Maf (42), we determined whether IL-6 controls c-Maf expression in Tfh and Tfh10 cells. In aged IL-6-deficient (IL6-KO) mice, the percent of Tfh and Tfh10 cells that express CD153 was reduced (Figure 4A).…”

Section: Il-6 Controls Cd153 Expression Through C-mafmentioning

confidence: 98%

Elevated CD153 Expression on Aged T Follicular Helper Cells is Vital for B cell Responses

Thomas

Wayman

Almanan

et al. 2023

Preprint

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Our recent data showed that an aberrant IL-10-producing T follicular helper population (Tfh10) accumulates dramatically with age and is associated with age-related declines in vaccine responsiveness. Through single cell RNA sequencing and chromatin accessibility analysis of IL-10+ and IL-10- memory CD4+ T cells from young and aged mice, we identified increased expression of CD153 on aged Tfh and Tfh10 cells. Mechanistically, we linked inflammaging (increased IL-6 levels) to elevated CD153 expression of Tfh cells through c-Maf. Surprisingly, blockade of CD153 in aged mice significantly reduced their vaccine-driven antibody response, which was associated with decreased expression of ICOS on antigen-specific Tfh cells. Combined, these data show that an IL-6/c-Maf/CD153 circuit is critical for maintaining ICOS expression. Thus, although overall Tfh-mediated B cell responses are reduced in the context of vaccines and aging, our data suggest that elevated expression of CD153 on Tfh cells potentiates the remaining Tfh function in aged mice.

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IL-6 can singlehandedly drive many features of frailty in mice

Cited by 16 publications

References 34 publications

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

IL-27 skews TNF-alpha-induced inflammatory microenvironment in keratinocytes

Elevated CD153 Expression on Aged T Follicular Helper Cells is Vital for B cell Responses

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