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

International audienceResident 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 muscle and MacL in the lamina propria, each 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 an anti-inflammatory profile, whereas MacL macrophages 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. Macrophage depletion 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 responses to an exceedingly common infection in a largely overlooked organ, the bladder

Le rôle fonctionnel et les différences liées au sexe des macrophages résidents dans la vessie lors d'une infection urinaire

Les infections urinaires (IU) sont la 2eme infection la plus fréquente, touchent surtout les femmes et sont principalement causées par E. coli uropathogène (UPEC). Les macrophages, dans la vessie sont les principales cellules pour acquérir l’UPEC pendant l’IU. On a identifié deux types de macrophages dans la vessie avec des profils d'expression distincts. Étant donné leur localisation distincte, on les a appelés MacM (muscle) et MacL (lamina propria). Pendant l'IU, les MacL meurent, tandis que les MacM acquièrent plus d’UPEC et deviennent anti-inflammatoire. Après la résolution, les macrophages sont partiellement remplacés par des cellules dérivées de monocytes. L'épuisement de macrophages avant une 2eme l’IU est en corrélation avec une réponse immunitaire de type 1 et une meilleure résolution. En étudiant les différences entre les sexes en matière d’IU, on a découvert que si les deux sexes sont également colonisés, les souris femelles présentent une réponse inflammatoire plus robuste que les souris mâles, qui n’éliminent pas l’IU. La testostérone ou la neutralisation de l'IL-17 chez les souris femelles annule la résolution de l’IU. Chez les deux sexes, l'estradiol augmente la phagocytose par les cellules immunitaires et non immunes. Ensemble, mes travaux font progresser nos connaissances sur la réponse immunitaire à l’IU chez les deux sexes.Urinary tract infections (UTI) are the second most common infection, predominantly impact women, and are primarily caused by uropathogenic E. coli (UPEC). Macrophages, the largest population of immune cells in the bladder, are the main antigen-presenting cells to acquire bacteria during UTI. We identified two macrophage subsets resident in the bladder with distinct RNA and protein expression profiles. Given their distinct localization, we named them MacM (muscle) and MacL (lamina propria). During UTI, MacL macrophages die rapidly, while MacM macrophages acquire more bacteria and polarize to an anti-inflammatory profile. After resolution of infection, macrophages are partially replaced by monocyte-derived cells, taking on expression profiles. Macrophage subset depletion prior to a second infection correlates with a greater type 1 immune response and improved bacterial clearance. Investigating immune-related sex differences in UTI, we found that while both sexes are equally colonized with UPEC, female mice mount a more robust inflammatory response than male mice, which fail to clear infection. Testosterone treatment or IL-17 neutralization in female mice abrogates resolution of infection. In both sexes, estradiol increases bacterial burden and uptake by immune and non-immune cells during UTI. Together, my work advances our knowledge of the immune response to UTI in both sexes

Bladder resident macrophages: Mucosal sentinels

International audienceMacrophages are instrumental in the response to infectious and noninfectious diseases, however, their role in the bladder is poorly understood. Indeed, the bladder is a mucosal tissue frequently overlooked in research, despite the prevalence of illnesses such as urinary tract infection and bladder cancer. Notably, bladder tissue macrophages are among the most populous resident immune cells in this organ and recent studies support that resident macrophages and infiltrating monocytes play nonredundant roles in response to infection, immunotherapy, and inflammation. Advancing our understanding of macrophage behavior in the bladder is complicated by the difficulty in obtaining tissue-resident cells. Surmounting this challenge, however, for a greater understanding of macrophage ontology, impact on innate and adaptive immunity, and regulation of homeostasis, will ultimately contribute to better therapies for common afflictions of the bladder

Tissue-resident memory T cells mediate mucosal immunity to recurrent urinary tract infection

International audienceUrinary tract infection (UTI) is one of the most prevalent human bacterial infections. New therapeutic approaches, including vaccination and immunotherapy, are urgently needed to combat the rapid global dissemination of multidrug-resistant uropathogens. Development of therapies is impeded by an incomplete understanding of memory development during UTI. Here, we found that reducing bacterial load early in infection, by reducing the inoculum or with antibiotics after infection, completely abrogated the protective memory response. We observed a mixed T helper (T H ) cell polarization, composed of T H 1, T H 2, and T H 17 T cells, among T cells infiltrating the bladder during primary infection. Thus, we hypothesized that reducing antigen load altered T H cell polarization, leading to poor memory. Unexpectedly, however, T H cell polarization was unchanged in these scenarios. Instead, we uncovered a population of tissue-resident memory (T RM ) T cells that was significantly reduced in the absence of sufficient antigen. Demonstrating that T RM cells are necessary for immune memory, transfer of lymph node– or spleen-derived infection-experienced T cells to naïve animals did not confer protection against infection. Supporting that T RM cells are sufficient to protect against recurrent UTI, animals depleted of systemic T cells, or treated with FTY720 to block memory lymphocyte migration from lymph nodes to infected tissue, were equally protected compared with unmanipulated mice against a second UTI. Thus, we uncovered an unappreciated key role for T RM cells in the memory response to bacterial infection in the bladder mucosa, providing a target for non–antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI

The impact of biological sex on diseases of the urinary tract

International audienceBiological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues

A Shape Sensing Mechanism driven by Arp2/3 and cPLA 2 licenses Dendritic Cells for Migration to Lymph Nodes in Homeostasis

Motile cells such as immune and cancer cells experience large deformation events that result from the physical constraints they encounter while migrating within tissues or circulating between organs. It has become increasingly clear that these cells can survive and adapt to these changes in cell shape using dedicated shape sensing pathways. However, how shape sensing impacts their function and fate remains largely unknown. Here we identify a shape sensing mechanism that couples cell motility to expression of CCR7, the chemokine receptor that guides immune cells to lymph nodes. We found that this mechanism is controlled by the lipid metabolism enzyme cPLA 2 , requires an intact nuclear envelop and exhibits an exquisitely sensitive activation threshold tuned by ARP2/3 and its inhibitor Arpin. We further show that shape sensing through the ARP2/3-cPLA 2 axis controls Ikkβ-NFκB-dependent transcriptional reprogramming of dendritic cells, which instructs them to migrate to lymph nodes in an immunoregulatory state compatible with their homeostatic tolerogenic function. These results highlight that the cell shape changes experienced by motile cells evolving within the complex environment of tissues can dictate their behavior and fate

Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes

International audienceImmune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA 2 , requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKβ–NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity

The immune response to infection in the bladder

International audienceThe bladder is continuously protected by passive defences such as a mucus layer, antimicrobial peptides and secretory immunoglobulins; however, these defences are occasionally overcome by invading bacteria that can induce a strong host inflammatory response in the bladder. The urothelium and resident immune cells produce additional defence molecules, cytokines and chemokines, which recruit inflammatory cells to the infected tissue. Resident and recruited immune cells act together to eradicate bacteria from the bladder and to develop lasting immune memory against infection. However, urinary tract infection (UTI) is commonly recurrent, suggesting that the induction of a memory response in the bladder is inadequate to prevent reinfection. Additionally, infection seems to induce long-lasting changes in the urothelium, which can render the tissue more susceptible to future infection. The innate immune response is well-studied in the field of UTI, but considerably less is known about how adaptive immunity develops and how repair mechanisms restore bladder homeostasis following infection. Furthermore, data demonstrate that sex-based differences in immunity affect resolution and infection can lead to tissue remodelling in the bladder following resolution of UTI. To combat the rise in antimicrobial resistance, innovative therapeutic approaches to bladder infection are currently in development. Improving our understanding of how the bladder responds to infection will support the development of improved treatments for UTI, particularly for those at risk of recurrent infection