Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection

Scharff, Anna Zychlinsky; Rousseau, Matthieu; Mariano, Lívia Lacerda; Canton, Tracy; Consiglio, Camila Rosat; Albert, Matthew L.; Fontes, Magnus; Duffy, Darragh; Ingersoll, Molly A.

doi:10.1172/jci.insight.122998

Cited by 65 publications

(93 citation statements)

References 72 publications

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“…Innate immune cells, including neutrophils, eosinophils, and immature MHC IImonocyte-derived cells were all increased 10-100 times over naïve mice in both sexes (Figure 7B). Interestingly, there were no differences in infiltration of these populations between the sexes, in contrast to what we reported in the context of urinary tract infection, in which female mice have a significantly greater number of immune cells present in their bladders during infection (Zychlinsky Scharff et al, 2019). APCs, including MHC II + monocyte-derived cells, resident macrophages, and both subsets of DCs were significantly increased over numbers in naïve mice in both sexes ( Figure 7C).…”

Section: More Tumor Antigen-specific T Cells Infiltrate Male Bladderscontrasting

confidence: 62%

“…Typically, only female mice are used for the MB49 mouse model as catheterization of male mice is reported to be unattainable by many preclinical bladder studies (El Behi et al, 2013;Hagberg et al, 1983;Oliveira et al, 2009;Olson et al, 2016;Seager et al, 2009). Given that more men than women develop bladder cancer, and that sex differences contribute to this bias in incidence (Kaneko and Li, 2018), we used a male mouse intravesical instillation protocol that we previously optimized to measure sex-specific differences in innate immunity to urinary tract infection (Zychlinsky Scharff et al, 2017;Zychlinsky Scharff et al, 2019). We implanted female and male mice with MB49 to determine whether sex differences impact immunity or response to BCG.…”

Section: Bcg Vaccination Increases Immune Cell Infiltration In Combinmentioning

confidence: 99%

“…Our goal for this study was to develop an optimized preclinical bladder cancer model in which we could assess the influence of immunotherapy on tumor-specific immunity in both sexes. As bladder cancer is approximately three times more common in men than in women, and innate bladder mucosal responses differ between the sexes in infection, we used female and male mice in both models to uncover potential sex-based differences in tumor immunity (Antoni et al, 2017;Zychlinsky Scharff et al, 2019). To develop these models, we incorporated a known model antigen into two well-established models of bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

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Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Rousseau

O'Brien

Antequera

et al. 2020

Preprint

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Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumorspecific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model. We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations.Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8 + T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy and that these cells had the highest levels of the exhaustion marker PD-1. We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men.

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Section: More Tumor Antigen-specific T Cells Infiltrate Male Bladderscontrasting

confidence: 62%

Section: Bcg Vaccination Increases Immune Cell Infiltration In Combinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Rousseau

O'Brien

Antequera

et al. 2020

Preprint

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“…As we observed fewer eosinophils in macrophage-depleted mice during challenge infection, and our previous work demonstrated that type 2 immune response-related cytokines are expressed early in UTI (Zychlinsky Scharff et al, 2019), we assessed the polarity of the T cell response to challenge infection (gating strategy, Figure S4). Macrophage depletion did not alter the infiltration of T regulatory cells, or Th2 or Th17 T helper subsets (Figure 7D).…”

Section: Depleting Macrophages Leads To a Th1 Biased Immune Response mentioning

confidence: 99%

“…While the origin and maintenance of bladder-resident macrophages is currently unknown, these macrophages do play a role in the response to urinary tract infection (UTI), which impacts up to 50% of all women at some point in their lifetimes (Foxman, 2002;Lacerda Mariano and Ingersoll, 2018). The immune response to uropathogenic Escherichia coli (UPEC) infection in the bladder is characterized by robust cytokine expression leading to rapid infiltration of large numbers of neutrophils and classical Ly6C + monocytes Haraoka et al, 1999;Ingersoll et al, 2008;Mora-Bau et al, 2015;Shahin et al, 1987;Zychlinsky Scharff et al, 2019). Although essential to bacterial clearance, neutrophil and monocyte infiltration likely also induce collateral tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder

Mariano

Rousseau

Varet

et al. 2020

Preprint

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Resident macrophages are abundant in the bladder, playing key roles in immunity to uropathogens. Yet, whether they are heterogeneous, where they come from, and how they respond to infection remain largely unknown. We identified two macrophage subsets in mouse bladders, MacM in the muscle and MacL in the lamina propria, with distinct protein expression and transcriptomes. Using a urinary tract infection model, we validated our transcriptomic analyses, finding that MacM macrophages phagocytosed more bacteria and polarized to a more anti-inflammatory profile, whereas the MacL subset died rapidly during infection. During resolution, monocyte-derived cells contributed to tissue-resident macrophage pools and both subsets acquired transcriptional profiles distinct from naïve macrophages. Depletion of these altered macrophages resulted in the induction of a type 1 biased immune response to a second urinary tract infection, improving bacterial clearance. Our study uncovers the biology of resident macrophages and their response to an exceedingly common infection in a largely overlooked organ, the bladder.

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Group 3 Innate Lymphoid Cells Protect the Host from the Uropathogenic Escherichia coli Infection in the Bladder

Huang

et al. 2022

Advanced Science

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Innate lymphoid cells (ILCs) are crucial in orchestrating immunity and maintaining tissue homeostasis in various barrier tissues, but whether ILCs influence immune responses in the urinary tract remains poorly understood. Here, bladder‐resident ILCs are comprehensively explored and identified their unique phenotypic and developmental characteristics. Notably, bladder‐resident ILCs rapidly respond to uropathogenic Escherichia coli (UPEC) infection. It is found that ILC3 is necessary for early protection against UPEC infection in the bladder. Mechanistically, UPEC infection leads to interleukin (IL)‐1β production in the bladder via a MyD88‐dependent pathway, which promotes ILC3 activation. ILC3‐expressed IL‐17A further recruits neutrophils and controls UPEC infection in the bladder. Together, these results demonstrate a critical role for bladder ILCs in the host defense against UPEC infection.

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Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection

Cited by 65 publications

References 72 publications

Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder

Group 3 Innate Lymphoid Cells Protect the Host from the Uropathogenic Escherichia coli Infection in the Bladder

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