Upon detecting pathogen invasion, urinary tract epithelial cells promptly mobilize resident tissue cells or circulating immune cells to the infection site via signaling pathways for bacterial clearance ( Figure 2 ). Neutrophils are the primary innate immune cells in fighting urinary tract infections and are vital for controlling early UPEC-induced infections (Hayes and Abraham, 2016; Ashkar et al., 2008). Neutrophil recruitment can be initiated by inflammatory mediators from leukocytes in the infected tissue or cytokines generated through intracellular signaling activated by Toll - like receptor 4 (TLR4) on bladder epithelial cell surfaces and the cytoplasmic Toll/IL - 1 receptor homology domain (TIR) (Yu et al., 2019; Hannan et al., 2010; Billips et al., 2007). The released cytokines like IL - 6, IL - 8, and TNF - α show elevated expression levels correlating with bacterial clearance. Notably, IL - 8 is the main chemokine directing neutrophils to the infection site (Bowyer et al., 2022). After infection, bladder epithelial cells quickly upregulate P - selectin and E - selectin, two adhesion molecules that cooperate to optimize neutrophil recruitment (Phillipson and Kubes, 2011; Petri et al., 2008).

When UPEC invades the kidneys, cytokines secreted by tubular epithelial cells, resident dendritic cells, or tissue - resident macrophages also recruit neutrophil (Bottek et al., 2020). The chemokine receptors CXCR1 and CXCR2, highly expressed on neutrophil surfaces, enable their recruitment to kidney infection sites by CXCL1 and CXCL (Roche et al., 2007). For example, CXCL2 secreted by Ly6C - macrophages can activate MMP - 9 on circulating neutrophil surfaces, allowing them to infiltrate epithelial tissues (Schiwon et al., 2014). Research shows that in children prone to pyelonephritis, CXCR1 expression in neutrophils is lower than in age - matched controls (Gabriela et al., 1997), suggesting susceptibility to pyelonephritis may be related to impaired neutrophil recruitment ability. Additionally, CXCR2 knockout mice have a higher chance of developing pyelonephritis, renal abscesses, and renal scarring when infected with UPEC, potentially leading to sepsis. Neutrophil - deficient mice also show a similar trend, indicating that the absence of CXCR2 is closely related to delayed neutrophil recruitment and reduced bacterial killing efficiency (Svensson et al., 2011). These findings suggest that CXCL1 and CXCL2 are crucial for neutrophil recruitment to the kidneys and that neutrophil recruitment is essential for the kidneys’ anti - infective response.

Neutrophils primarily exert their anti - infection effects through three mechanisms: phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs), which consist of DNA released from neutrophils along with proteins that aid in pathogen capture and killing (Rosales, 2018). Their mechanisms are as follows: (1) Neutrophils are potent phagocytic cells that rapidly engulf pathogens, and this phagocytic activity is enhanced by the complement system and immunoglobulin G (IgG) antibodies (Segal, 2005). (2) The cytoplasmic granules of neutrophils are critical for pathogen destruction. These granules are classified into four types: primary, secondary, tertiary, and secretory granules (Sheshachalam et al., 2014; Paige, 2006). Primary granules contain myeloperoxidase (MPO) and neutral protease G (NPG), which directly kill and digest pathogens. Secondary granules (specific granules) contain lactoferrin, which sequesters iron and copper, limiting microbial growth. Tertial granules (gelatinase granules) include matrix metalloproteinase - 9 (MMP - 9), essential for degrading the extracellular matrix and activating interleukin - 1 beta (IL - 1β). Secretory granules contain serum albumin and pre - formed cytokines (Sheshachalam et al., 2014). During degranulation, granules are released into the extracellular environment in a specific order: secretory granules, tertiary granules, secondary granules, and finally, primary granules, contributing to their bactericidal effectsHannan, 2025). However, the efficacy of these mechanisms decreases significantly in blood flow. To address this, neutrophils have evolved NETs. (3) NETs form a web - like structure of DNA released from neutrophils, coated with neutrophil proteases (like elastase), antimicrobial molecules (like histones), and other toxic components for pathogen clearance (Kolaczkowska et al., 2015; Phillipson and Kubes, 2011). These components effectively trap and kill pathogens in the bloodstream. NETs formation begins with nuclear membrane degradation and DNA release triggered by reactive oxygen species (ROS) generated by neutrophils (Lin et al., 2024; Cotzomi-Ortega et al., 2024). NETs play a crucial role in controlling invasive infections. In experiments with mice treated with exogenous DNase to degrade NETs, an increase in bacteremia incidence and bacteria escape from the skin were observed (Yipp et al., 2012). In conclusion, neutrophils, as significant innate immune cells, play a crucial role in combating urinary tract pathogens.

In addition to neutrophils, macrophages and dendritic cells are also essential for the body’s defense against urinary tract pathogen invasion ( Figure 2 ). When pathogens invade bladder epithelial cells, macrophages respond rapidly and show strong phagocytic abilities, limiting pathogen proliferation and spread through phagocytosis. Dendritic cells also have the capacity to phagocytose pathogens, and this ability gradually increases within 24 hours post - infection (Mass et al., 2023). However, some studies indicate that in the presence of both macrophages and dendritic cells, the phagocytic function of dendritic cells may be suppressed by macrophage (Bowyer et al., 2022). Moreover, the competition between them for phagocytosing bacteria may lead to a decrease in the antigen - presenting efficiency of dendritic cells, thus weakening the adaptive immune response (Mora-Bau et al., 2015). This implies that their interactions can affect the scale and degree of both innate and adaptive immune responses. The complex network of dendritic cells and macrophages in renal tissue can detect the state of the renal interstitium by sensing self - antigens, danger signals, as well as pathogen - associated molecular patterns (PAMPs) and damage - associated molecular patterns (DAMPs) released by bacteria in the glomeruli and renal tubules (Mariano and Ingersoll, 2020; Hayes and Abraham, 2016a, Weisheit et al., 2015; Sedin et al., 2019; Hayes and Abraham, 2016). This sentinel function enables them to coordinate TLR4 - mediated antimicrobial defense programs.

In the early stages of infection, uropathogenic Escherichia coli (UPEC) releases PAMPs and DAMPs into the urine and surrounding tissues, which can affect the resident macrophage population and the recruited Ly6C + monocyte population, promoting macrophage differentiation toward the “M2 type” (Wang et al., 2014; Davies et al., 2013; Galli et al., 2011). Tissue - resident macrophages recruit Ly6C + monocyte - derived macrophages to the bladder lamina propria by activating the NF - κB signaling pathway (Mariano et al., 2020). These macrophages, through the expression of iNOS and inflammatory cytokines such as TNF and IL - 1β, stimulate the secretion of CXCL2 from Ly6C - macrophages, facilitating the recruitment of dendritic cells and circulating neutrophils into the epithelial tissue to combat infection (Ruiz-Rosado et al., 2021; Berry et al., 2017; Schiwon et al., 2014; Tsou et al., 2007). In studies on mice with pyelonephritis, depleting Ly6C + macrophages and reducing the secretion of inflammatory cytokines and chemokines can stop the increased recruitment of circulating monocytes to the kidneys. Notably, with the reduction of monocytes, the bacterial load in the kidneys decreases, suggesting that Ly6C + macrophages derived from monocytes may have a dual role in promoting inflammation and bacterial dissemination during pyelonephritis (Ruiz-Rosado et al., 2021).

Recently, resident macrophages in the bladders of female C57BL/6 mice have been classified into two functionally distinct populations: muscle layer resident macrophages and lamina propria resident macrophages. Both populations can be supplemented by recruiting monocytes (Mariano et al., 2020). RNA sequencing analysis shows an increased expression of genes related to endocytosis and the formation of phagosomes and lysosomes in muscle layer resident macrophages. This suggests that these macrophages may have enhanced anti - inflammatory and phagocytic activities during early urinary tract infections. In contrast, lamina propria resident macrophages show high expression of chemokines and genes related to TLR signaling pathways, indicating a greater propensity for pro - inflammatory responses (Mariano et al., 2020). Notably, the pro - inflammatory capability of lamina propria resident macrophages is similar to that of recruited Ly6C + circulating monocytes in the bladder lamina propria, suggesting that Ly6C + circulating monocytes could be precursors to lamina propria resident macrophages. The latest research has demonstrated that resident macrophages can release Macrophage Extracellular Traps (METs), which are similar to neutrophil extracellular traps (NETs), for bacterial clearance (Hannan, 2025). However, there is still relatively little research on resident macrophages in the bladder, which may become a new direction for studying the anti-infective immunity of the bladder.

In addition to neutrophils, macrophages, and dendritic cells, other innate cells in the urinary tract immune network also play significant roles. Mast cells (MCs), as bladder immune sentinel cells, are mainly located in the bladder lamina propria and detrusor muscle ( Figure 2 ). During early infection, mast cells show notable proliferation and migration towards the infection site and can accelerate neutrophil recruitment by releasing pre - stored granule mediators from their cytoplasm (Doener et al., 2013; Siebenhaar et al., 2007; Austen, 2001; Roger et al., 2001). Research shows that mast cell absence impairs neutrophil recruitment and activation, affecting bacterial clearance (Doener et al., 2013). Moreover, inflammatory factors in cytoplasmic granules, like tumor necrosis factor, can also speed up dendritic cell recruitment and adaptive immune response formation (Shelburne et al., 2009). Additionally, mast cells are crucial for promoting homeostasis and tissue recovery after infection resolution (Choi et al., 2016). Recent studies indicate that several hours after bladder infection, mast cells express large amounts of the immunosuppressive cytokine IL - 10, corresponding to bladder epithelial cell shedding and repair (Chan et al., 2013). This suggests that mast cell - derived IL - 10 may facilitate bladder epithelial cell recovery; however, this immunosuppressive phenomenon may lead to premature elimination of adaptive immune responses, affecting the pathological process (Chan et al., 2013). Thus, mast cells have dual “pro - inflammatory” and “anti - inflammatory” roles in UTIs, and regulating these functions influences the UTI course. However, at present, the research regarding the role of mast cells in urinary tract infections (UTIs) is relatively scarce, and numerous aspects remain unresolved. For instance, how do mast cells accomplish the transition between the “pro - inflammatory” and “anti - inflammatory” states during the course of UTIs? Does the interleukin - 10 (IL - 10) secreted by them play a pivotal role? Does it exert its functions in UTIs via alternative pathways? And so forth. All these queries necessitate further in - depth investigation.

Innate lymphoid cells (ILCs) and innate - like T cells also have a role in the response to UTIs. Innate - like lymphoid cells are equivalent effector cells to T cells, residing and integrated within tissues, lacking antigen receptors on their surfaces like T and B cells (Artis and Spits, 2015; Naskar and Choi, 2024). They present and process antigens via major histocompatibility complex class II (MHC II) molecules, indirectly regulating antigen - specific T cells (Vivier et al., 2018; Naskar and Choi, 2024). Functionally, ILCs can be divided into five subgroups: natural killer (NK) cells, ILC1, ILC2, ILC3, and lymphoid tissue inducer (LTi) cells (Vivier et al., 2018; Liu et al., 2025; Huang et al., 2022). Among them, NK cells mainly reflect CD8 + T cell functions, while ILC1, ILC2, and ILC3 represent Th1, Th2, and Th17 type T cells respectively. Notably, NK cells make up about 2% of bladder immune cells in healthy juvenile mice and can kill pathogens by releasing perforin, granzymes, and pro - inflammatory cytokines (Bowyer et al., 2022). However, the relative contributions of NK cell subpopulations in the bladder are unclear. Additionally, recent studies show that ILC3s are highly enriched in mucosal tissues, can regulate Th17 cell responses and participate in innate immune responses against extracellular bacteria (Hepworth et al., 2013). This includes inducing epithelial cells to express antimicrobial peptides via IL - 22 production and enhancing antiviral proteins for INF - λ signaling to resist pathogen invasion (Vivier et al., 2018). Some studies report sex differences in ILC3 populations, with more ILC3s in normal male juvenile bladders than in females, but a more pronounced increase in females after UPEC challenge (Zychlinsky et al., 2019). This may indicate a sex - related distribution and proliferation of ILC3s, but further investigation is needed to explore links to UTI incidence and prognosis.

Mucosal - associated invariant T (MAIT) cells are a unique subset of unconventional T cells, including γδ - T cells, natural killer T (NKT) cells, and MAIT cells, found mainly in barrier tissues like the gut, skin, and lungs, where they express T cell receptors (TCR) (Ribot et al., 2021). Notably, γδ - T cells are important for eliminating bacteria from the bladder, probably due to high IL - 17 levels. Research shows that granulocyte colony - stimulating factor (G - CSF), which regulates neutrophil maturation and release, is influenced by IL - 17 - producing γδ - T cells (Ley et al., 2006). This implies a significant role of γδ - T cells in neutrophil recruitment. However, current studies have not clearly established the role of IL - 17A secreted by γδ - T cells in adaptive immune responses (Chamoun et al., 2020). MAIT cells, associated with the microbiome, are activated by recognizing riboflavin metabolites produced by bacteria, and are abundant in mucosal tissues (Gibbs et al., 2016; Booth et al., 2015; Terpstra et al., 2020). Evidence shows that MAIT cells in mouse UTI models migrate to the bladder during infection, reducing bacterial load. A study on human UTIs also found MAIT cells in patient urine (Cui et al., 2015). These suggest that MAIT cells may play a significant role in human UTIs (Dias et al., 2016). Recent research shows that MAIT cells can reside in renal tissue by expressing CD69 and CD103 (Law et al., 2019), and when activated, secrete cytokines like IL - 2, IL - 17A, and granulocyte - macrophage colony - stimulating factor (GM - CSF) (Terpstra et al., 2020). These cytokines may act as a first line of defense against pathogen invasion in the kidneys. Although the mechanisms involving MAIT cells in UTIs are under - explored, existing evidence suggests they may be critical for the body’s defense against pathogen invasion during UTIs.

Compared with the innate immune system, which rapidly responds to pathogens by recognizing pathogen - associated molecular patterns (PAMPs) or damage - associated molecular patterns (DAMPs) non - specifically, the activation and establishment of the adaptive immune system, characterized by strong specificity and immunological memory, takes a longer time (Neugent et al., 2020) ( Figure 2 ). T cells and B cells, as core components of the adaptive immune system, play important roles in fighting urinary tract infections (UTIs) (Song and Deng, 2020). During a UTI, uropathogenic Escherichia coli (UPEC) adheres to urinary tract epithelial cells and invades tissues, triggering a series of signaling pathways and host defense mechanisms that activate immune cells, including T cells, to enter the infection site and combat pathogen invasion (Isaacson et al., 2017). Research shows that after a UTI begins, the number of CD4 + T cells in the bladders of female mice significantly increases (Scharff et al., 2019), with various subpopulations detected, including Th1, Th2, Th17 cells, and regulatory T cells (Tregs) (Mariano et al., 2020). The emergence of Tregs reflects the host’s downregulation of immune responses to maintain the integrity of the urinary tract epithelium (Yu et al., 2019). Moreover, recent studies have revealed that T cells activated and migrated to the bladder after infection have limited ability to eliminate bacteria (Wu et al., 2020; Li et al., 2019; O’Brien et al., 2018); these T cells are more likely to secrete IL - 4, which promotes tissue repair, rather than IFN - γ, which is associated with bacterial clearance, suggesting a preferential differentiation towards the Th2 phenotype rather than the Th1 phenotype (Wu et al., 2020). Additionally, about 50% of CD11c + CD301b + dendritic cells in the bladder express OX40L, a molecule that preferentially polarizes CD4 + T cells towards the Th2 type (Schuijs et al., 2019; Wu et al., 2020). This cell differentiation tendency helps protect deeper bladder tissues from the harmful effects of salts, urea, and other substances in the urine when the epithelial cell shedding program is activated, but it also reduces the ability to eliminate bacteria in the bladder. This guided T cell differentiation indicates that the host balances antibacterial immune responses and repair processes when pathogens invade, aiming to resist pathogen entry and further infection with minimal damage.

The specific mechanisms of T cell - mediated anti - infective protection during urinary tract infections remain unclear. Activated Th1 and Th17 cells after infection may play a role in bacterial clearance by secreting cytokines IFN - γ and IL - 17, thereby further activating macrophages and CD8 + T cells or accelerating neutrophil recruitment (Mariano et al., 2020; Bowyer et al., 2022). Overall, research on adaptive T cells in the bladder is still in its early stages, and many related mechanisms remain undefined. As research on bladder immunity in urinary tract infections progresses, it is crucial to focus on the roles of different T cell subtypes, especially regulatory T cells, in anti - infective immunity in the bladder. Elucidating the mechanisms that maintain the delicate balance between limiting immune responses and promoting bacterial clearance will be crucial for future research. A deeper understanding of the roles of T cells in resisting urinary tract infections and the differentiation of memory T cells will not only help reveal the diversity of urinary tract immune responses but also assist in developing more effective treatment strategies and preventive vaccines for urinary tract infections.

Tissue - resident memory T (Trm) cells, a subset of memory T cells, consist of unique, non - migratory cell populations that permanently reside in organs like the skin, intestines, and lungs (Gebhardt et al., 2009) ( Figure 2 ). They play a crucial role in providing long - term immune protection (Longet and Paul, 2023).

In one study, researchers used lymphocyte - depleting antibodies to deplete systemic circulating T cells to verify the role of tissue - resident memory T cells in resisting recurrent urinary tract infections. The results showed that treated mice had similar anti - infection responses as untreated mice, with a sustained increase in T cell numbers detected in the bladders of treated mice (Rousseau et al., 2023). This finding emphasizes the important protective role of tissue - resident memory T cells in establishing adaptive immunity in the bladder. Moreover, research has found that CD4 + tissue - resident memory T cells are more abundant than CD8 + tissue - resident memory T cells in healthy human kidneys (van der Putten et al., 2021; Krebs et al., 2020). However, in patients with glomerulonephriti, the amounts of CD4 + and CD8 + tissue - resident memory T cells in the kidneys are nearly equal (Lisboa et al., 2020; Krebs et al., 2016). This indicates that during glomerulonephritis, there may be a greater increase in the number of CD8 + tissue - resident memory T cells in the human kidneys, although the reasons for this disproportional proliferation remain unclear. In a mouse model of pyeloneinitis, the number of renal tissue - resident memory T cells also showed a significant increase (Krebs et al., 2020). However, there is currently no data to support whether CD4 + and CD8 + tissue - resident memory T cells show different degrees of increase in this model. It is unclear how renal tissue - resident memory T cells adapt to their environment; however, studies have shown that liver tissue - resident memory T cells upregulate hypoxia - inducible factor pathways to adapt to the hypoxic conditions in the liver (Kim et al., 2020). Similarly, renal tissue - resident memory T cells in hypoxic environments may adapt through similar mechanisms and contribute to anti - infective immunity, providing a new research direction for studying the adaptive immune mechanisms within the bladder during urinary tract infections.

After infection onset, dendritic cells and macrophages present antigens to B cell germinal centers by phagocytosing pathogens, leading to B cell activation. Activated B cells can differentiate into either effector B cells or memory B cells ( Figure 2 ). Effector B cells (plasma cells) combat pathogens by producing antibodies, while memory B cells can quickly initiate adaptive immune responses upon re - exposure to the same pathogen (Seifert and Küppers, 2016; Hawas et al., 2023). Additionally, after B cell activation, these cells can influence T cell activation through antigen presentation, provision of co - stimulatory factors, and secretion of cytokine (Petersone et al., 2018; Bishop, 2016). Among these, the co - stimulatory factor OX40 ligand (OX40L) is a crucial regulatory molecule for the proliferation and survival of T cells, promoting the differentiation of CD4 + T cells towards the Th2 phenotype (Rogers et al., 2001; Linton et al., 2003). Furthermore, recent research on tissue - resident B cells has categorized them into two subsets: B - 1 and B - 2 cells. Notably, B - 1 cells, which are enriched in the pleural and peritoneal cavities, have also been found in damaged and infected skin, lungs, and kidneys (Suchanek et al., 2023; Denton et al., 2019; Stark et al., 2018). These B - 1 cells form a significant part of the pool of tissue - resident B cells in these organs [137]. Studies have shown a negative correlation between the number of tissue - resident B cells in the kidneys and susceptibility to urinary tract infections (Suchanek et al., 2023). Moreover, the expression of chemokine transcripts for neutrophil and monocyte recruitment is elevated in the kidneys of B cell - deficient mice (Suchanek et al., 2023), suggesting that tissue - resident B cells may inhibit renal antibacterial immunity and affect the recruitment of circulating immune cells to infected organs.

Single - cell sequencing results also reveal the presence of plasma cells producing secretory IgA in the urethral lamina propria of healthy mice, with secretion levels increasing with age (Ligon et al., 2020). It is unclear whether the observed changes in cell proportion and secretion levels contribute to the increased prevalence of urinary tract infections in the elderly or if they reflect a response to repeated infections. However, the role of secretory IgA in bladder anti - infection remains uncertain. Thus, although some studies have investigated the role of B cells in urinary tract infection defenses, their exact protective roles and mechanisms need further investigation to clarify.