Beyond barrier immunity: IL-17 safeguards the renal epithelium

IL-17 is widely recognized as a central mediator of antifungal immunity at barrier surfaces (Dos Santos Dias and Lionakis, 2024; Gaffen and Moutsopoulos, 2020). In this issue of The Journal of Experimental Medicine, Choi and colleagues identify a tissue-type plasminogen activator (tPA)–LDL receptor–related protein 1 (LRP1) signaling pathway that protects renal tubular epithelial cells from apoptosis during systemic Candida albicans infection (Choi et al., 2026). Their work provides mechanistic insight into how IL-17 preserves renal epithelial integrity and kidney function independently of fungal clearance, further expanding the notion that successful host defense relies not only on eliminating pathogens but also on limiting the tissue damage they inflict.

The role of IL-17 in mucosal antifungal immunity is well-established. Produced by multiple mucosal lymphoid populations, including Th17 cells, γδ T cells, and group-3 innate lymphoid cells, IL-17 acts on epithelial cells to induce neutrophil-recruiting chemokines and antimicrobial peptides that restrict fungal growth and maintain barrier integrity (Dos Santos Dias and Lionakis, 2024; Gaffen and Moutsopoulos, 2020). The importance of this pathway is underscored by convergent evidence from human genetics and clinical medicine. Patients with inherited defects affecting IL-17 immunity, individuals with neutralizing autoantibodies against IL-17 cytokines, and those receiving therapeutic IL-17 blockade are susceptible to mucosal candidiasis (Lionakis et al., 2023; Puel et al., 2011), establishing IL-17 as an indispensable mediator of antifungal immunity at barrier surfaces.

Less appreciated, however, is that IL-17 also contributes to host defense during experimental disseminated candidiasis. Following hematogenous dissemination, C. albicans exhibits a striking tropism for the kidney in both mice and humans, where fungal proliferation and inflammation culminate in acute kidney injury, a major determinant of mortality (Lionakis et al., 2011). In this setting, neutrophils and mononuclear phagocytes are the principal antifungal effector cells (Lionakis et al., 2023), whereas renal γδ T cells constitute the predominant source of IL-17 during infection (Ramani et al., 2018). Initial studies demonstrated that mice lacking IL-17 receptor signaling exhibit impaired renal neutrophil recruitment and function, increased renal fungal burden, and accelerated mortality, thereby extending the role of IL-17 beyond barrier immunity (Bär et al., 2014; Huang et al., 2004). Complementing these observations, C. albicans Lip2 suppresses renal IL-17 responses, thereby promoting fungal virulence during systemic candidiasis (Basso et al., 2022).

The story, however, did not end with neutrophils. Biswas and colleagues subsequently demonstrated that IL-17 receptor signaling within renal tubular epithelial cells is itself indispensable for protection during disseminated candidiasis (Ramani et al., 2018). Specifically, epithelial IL-17 receptor signaling activates the kallikrein–kinin system, limits tubular apoptosis, preserves kidney function, and improves mouse survival. Together, these studies established that IL-17 protects the kidney not only by promoting antifungal immunity but also by preserving renal epithelial integrity, yet the underlying molecular effectors that translate IL-17 signaling into epithelial protection remained incompletely defined.

Building on this framework, Choi and colleagues identify tPA as a downstream mediator of IL-17–dependent epithelial protection (Choi et al., 2026). Transcriptomic analyses of infected kidneys revealed reduced expression of Plat, the gene encoding tPA, in Il17ra^−/− mice. This reduction localizes to renal tubular epithelial and endothelial cells, where IL-17 and TNF synergistically induce tPA expression. Together, these findings position tPA downstream of inflammatory circuits activated within the Candida-infected kidney.

The biological importance of this observation rapidly becomes apparent in vivo. Mice lacking tPA exhibit increased mortality following systemic C. albicans infection. Pharmacologic blockade further distinguished the two major tPA receptors: inhibition of LRP1, but not annexin A2, exacerbated disease, demonstrating that the protective activity of tPA is mediated through LRP1 signaling. The authors further identify the dectin-1/CARD9 axis as an upstream regulator of LRP1 expression in renal tubular epithelial cells, linking fungal recognition to the tPA–LRP1 pathway. Collectively, these findings establish the physiological importance of the tPA–LRP1 axis during systemic candidiasis and set the stage for defining its mechanism of protection.

An elegant aspect of the study is the demonstration that tPA–LRP1-mediated protection is orchestrated by the renal epithelium itself. Using mice with conditional deletion of LRP1 in renal tubular epithelial cells, the authors show that epithelial-intrinsic signaling is required to preserve renal function during systemic candidiasis. Loss of tubular epithelial LRP1 resulted in exaggerated epithelial apoptosis, more severe tubular injury, elevated serum creatinine concentrations, and reduced mouse survival despite similar renal fungal burden and phagocyte recruitment. These findings distinguish the tPA–LRP1 axis from classical antifungal effector programs. Rather than influencing fungal clearance, this pathway appears to determine how well the kidney tolerates the inflammatory consequences of infection. Together with the earlier demonstration that IL-17 receptor signaling within tubular epithelial cells protects the kidney during systemic candidiasis (Ramani et al., 2018), these findings establish the renal epithelium as an active participant in antifungal host defense rather than a passive target of fungal invasion. Although the epithelial compartment clearly emerges as the dominant site of protection, the parallel induction of tPA in renal endothelial cells raises the possibility that vascular LRP1 signaling could also contribute to host defense, an open question for future studies using endothelial-specific conditional knockout mice.

Mechanistically, Choi and colleagues demonstrate that tPA engagement of LRP1 on renal tubular epithelial cells activates an ERK1/2-p90RSK signaling cascade that culminates in inhibitory phosphorylation of the pro-apoptotic protein Bad, providing a molecular explanation for how tPA–LRP1 signaling preserves epithelial viability during infection. Notably, these effects are independent of the canonical proteolytic activity of tPA. Traditionally viewed as a serine protease responsible for plasminogen activation and fibrinolysis, tPA occupies a complex position in host–pathogen interactions because microorganisms, including C. albicans, exploit host plasminogen activation systems to facilitate tissue invasion (Chen et al., 2020). Choi and colleagues elegantly dissociate these two functions by demonstrating that catalytically inactive tPA retains the ability to reduce epithelial apoptosis, preserve renal function, and improve mouse survival during systemic candidiasis. Thus, receptor-mediated signaling, rather than plasminogen activation, emerges as the principal mechanism underlying tPA-mediated renal epithelial protection during systemic candidiasis.

By identifying a molecular effector of IL-17–dependent epithelial protection, Choi and colleagues broaden our understanding of how this cytokine coordinates effective host defense during invasive fungal infection. Previous studies established that IL-17 protects the kidney during disseminated candidiasis through signaling within renal tubular epithelial cells (Ramani et al., 2018). Choi and colleagues now identify one molecular pathway through which IL-17 executes this epithelial protective program. More broadly, these findings illustrate how cytokines orchestrate host defense not only by regulating immune cell recruitment and effector function but also by inducing tissue-specific molecular effectors that preserve organ function during infection.

The study reinforces an increasingly important concept in infectious diseases: successful host defense reflects both pathogen resistance and disease tolerance (Dos Santos Dias and Lionakis, 2026). While classical antifungal immunity has focused largely on fungal clearance, the current work demonstrates that preservation of renal epithelial integrity can independently improve survival despite unchanged fungal burden. Rather than functioning as a conventional antifungal effector pathway, the tPA–LRP1 axis determines how well the infected kidney tolerates inflammatory injury. These findings further support the notion that limiting tissue damage represents a fundamental component of effective immunity, particularly during invasive fungal infections in which mortality often reflects progressive organ dysfunction in addition to uncontrolled fungal proliferation.

Importantly, the finding that catalytically inactive tPA retains its protective activity has potential translational implications. Selective engagement of LRP1 signaling may ultimately offer a means of preserving renal epithelial integrity without the bleeding risks associated with fibrinolytic therapy. Conversely, the study raises the possibility that therapeutic IL-17 blockade could inadvertently compromise IL-17–dependent epithelial protective programs, potentially exacerbating acute kidney injury during systemic candidiasis or other inflammatory renal disorders in which the tPA–LRP1 axis may contribute to tissue protection.

Finally, the work raises broader biological questions extending beyond systemic candidiasis. Whether IL-17 engages an analogous tPA-LRP1 tPA-LRP1 tissue-protective program in other organs remains unknown, but barrier epithelia such as the oral and intestinal mucosae represent attractive candidates given the well-established role of IL-17 in maintaining epithelial integrity and tissue homeostasis. Within the kidney, the biology of the tPA–LRP1 axis appears considerably more complex than previously appreciated. While the current study identifies tPA–LRP1 signaling as a mechanism that preserves renal epithelial integrity during systemic candidiasis, previous work implicated the same pathway in promoting renal fibrosis and exacerbating ischemia-reperfusion injury, illustrating how the same signaling pathway can exert opposing effects depending on the inflammatory context (Hu et al., 2007; Wang et al., 2025; Yang et al., 2002). Despite these contrasting roles, LRP1-mediated pro-survival effects have also been reported in fibroblasts and myofibroblasts (Hu et al., 2008), raising the possibility that the epithelial protective program identified here may reflect a broader cytoprotective function of this receptor. Collectively, by identifying the tPA–LRP1 axis as a downstream effector of IL-17–dependent epithelial protection, Choi and colleagues provide a framework for understanding how immune cytokines preserve organ integrity during systemic infection—a principle that may extend well beyond fungal disease.