Age-associated differences in macrophage response in a vaginal wound healing rat model

Menachem-Zidon, Ofra Ben; Parkes, Ilana; Chill, Henry H.; Reubinoff, Benjamin; Sandberg, Kathryn; Ji, Hong; Shveiky, David

doi:10.1007/s00192-020-04266-9

Cited by 12 publications

(13 citation statements)

References 26 publications

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“…Loss of natural lubrication can lead to epithelial damage during sexual intercourse, potentially increasing pathogen access to the underlying tissue. Furthermore, epithelial wound healing is compromised following menopause in animal models (Ben Menachem‐Zidon et al, 2020; Shveiky et al, 2020), at other mucosal sites (Engeland et al, 2009; Horng et al, 2017) and in cell culture (Patel, M. Unpublished).…”

Section: Changes In Epithelial Cells and Barrier Protection Induced B...mentioning

confidence: 99%

The impact of aging on innate and adaptive immunity in the human female genital tract

et al. 2021

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The aged population (>60 years old) is increasing rapidly and projected to grow to 1.4 billion by 2030, with women accounting for approximately 2/3 of individuals in this age group (He et al., 2016).With age, genitourinary infections and gynecological cancers increase, with profound effects on the morbidity and mortality of women (Gavazzi & Krause, 2002). Epidemiological studies show that urinary tract infections (UTI) and sexually transmitted infection (STI) rates increase in older women (CDC, 2016a(CDC, , 2016b, presenting a

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Section: Changes In Epithelial Cells and Barrier Protection Induced B...mentioning

confidence: 99%

The impact of aging on innate and adaptive immunity in the human female genital tract

et al. 2021

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“…Indeed, new data suggest that epidermal Arg1 also contributes to effective skin repair in rodents and humans (25). Our data now reveal a direct link between Arg1 and ageassociated delayed healing in the vagina, with significant clinical importance given the association between ageing, vaginal prolapse and recurrence following reconstructive surgery (13,18).…”

Section: Discussionmentioning

confidence: 69%

“…It is also clear that pelvic organs and their surrounding muscular and connective tissue support display broad estrogen receptor expression and are estrogen responsive ( 12 ). Age/estrogen-related tissue deterioration contributes to prolapse by weakening the levator ani muscle groups, uterosacral and cardinal ligaments and fibromuscular connective tissue of the vagina ( 13 ). Increased age and estrogen-deficiency is also a primary risk factor for poor tissue repair in rodents and humans ( 14 – 17 ).…”

Section: Introductionmentioning

confidence: 99%

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

et al. 2022

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Pelvic organ prolapse is a disorder that substantially affects the quality of life of millions of women worldwide. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Due to ineffective healing in the elderly, prolapse recurrence rates following surgery remain high. Therefore, there is an urgent need to elucidate the cellular and molecular drivers of poor healing in pelvic floor dysfunction to allow effective management and even prevention. Recent studies have uncovered the importance of Arginase 1 for modulating effective healing in the skin. We thus employed novel in vitro and in vivo vaginal injury models to determine the specific role of Arginase 1 in age-related vaginal repair. Here we show, for the first time, that aged rat vaginal wounds have reduced Arginase 1 expression and delayed healing. Moreover, direct inhibition of Arginase 1 in human vaginal epithelial cells also led to delayed scratch-wound closure. By contrast, activation of Arginase 1 significantly accelerated healing in aged vaginal wounds in vivo, to rates comparable to those in young animals. Collectively, these findings reveal a new and important role for Arginase 1 in mediating effective vaginal repair. Targeting age-related Arginase 1 deficiency is a potential viable therapeutic strategy to promote vaginal healing and reduce recurrence rate after surgical repair of pelvic organ prolapse.

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“…The polarization of macrophages into suitable types upon receipt of certain stimuli is necessary for effective tissue repair in many contexts. Dysregulation and prolonged macrophage response cause persistent inflammation and poor tissue repair seen in many diseases including BV, consequently increasing the risk of other pathogenic infections (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Tilapia Piscidin 4 (TP4) Reprograms M1 Macrophages to M2 Phenotypes in Cell Models of Gardnerella vaginalis-Induced Vaginosis

Liu

Chen

2021

Front. Immunol.

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Gardnerella vaginalis is associated with bacterial vaginosis (BV). The virulence factors produced by G. vaginalis are known to stimulate vaginal mucosal immune response, which is largely driven by activated macrophages. While Tilapia piscidin 4 (TP4), an antimicrobial peptide isolated from Nile tilapia, is known to display a broad range of antibacterial functions, it is unclear whether TP4 can affect macrophage polarization in the context of BV. In this study, we used the culture supernatants from G. vaginalis to stimulate differentiation of THP-1 and RAW264.7 cells to an M1 phenotype. The treatment activated the NF-κB/STAT1 signaling pathway, induced reactive nitrogen and oxygen species, and upregulated inflammatory mediators. We then treated the induced M1 macrophages directly with a non-toxic dose of TP4 or co-cultured the M1 macrophages with TP4-treated vaginal epithelial VK2 cells. The results showed that TP4 could not only decrease pro-inflammatory mediators in the M1 macrophages, but it also enriched markers of M2 macrophages. Further, we found that direct treatment with TP4 switched M1 macrophages toward a resolving M2c phenotype via the MAPK/ERK pathway and IL-10-STAT3 signaling. Conversely, tissue repair M2a macrophages were induced by TP4-treated VK2 cells; TP4 upregulated TSG-6 in VK2 cells, which subsequently activated STAT6 and M2a-related gene expression in the macrophages. In conclusion, our results imply that TP4 may be able to attenuate the virulence of G. vaginalis by inducing resolving M2c and tissue repair M2a macrophage polarizations, suggesting a novel strategy for BV therapy.

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Age-associated differences in macrophage response in a vaginal wound healing rat model

Cited by 12 publications

References 26 publications

The impact of aging on innate and adaptive immunity in the human female genital tract

The impact of aging on innate and adaptive immunity in the human female genital tract

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

Tilapia Piscidin 4 (TP4) Reprograms M1 Macrophages to M2 Phenotypes in Cell Models of Gardnerella vaginalis-Induced Vaginosis

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