Local Generation of Kynurenines Mediates Inhibition of Neutrophil Chemotaxis by Uropathogenic Escherichia coli

Abstract

During epithelial infections, pathogenic bacteria employ an array of strategies to attenuate and evade host immune responses, including the influx of polymorphonuclear leukocytes (PMN; neutrophils). Among the most common bacterial infections in humans are those of the urinary tract, caused chiefly by uropathogenic Escherichia coli (UPEC). During the establishment of bacterial cystitis, UPEC suppresses innate responses via multiple independent strategies. We recently described UPEC attenuation of PMN trafficking to the urinary bladder through pathogen-specific local induction of indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolic enzyme previously shown to have regulatory activity only in adaptive immunity. Here, we investigated the mechanism by which IDO induction attenuates PMN migration. Local tryptophan limitation, by which IDO is known to influence T cell longevity and proliferation, was not involved in its effect on PMN trafficking. Instead, metabolites in the IDO pathway, particularly L-kynurenine, directly suppressed PMN transepithelial migration and induced an attached, spread morphology in PMN both at rest and in the presence of chemotactic stimuli. Finally, kynurenines represent known ligands of the mammalian aryl hydrocarbon receptor (AHR), and UPEC infection of Ahr ؊/؊ mice recapitulated the derepressed PMN recruitment observed previously in Ido1 ؊/؊ mice. UPEC therefore suppresses neutrophil migration early in bacterial cystitis by eliciting an IDO-mediated increase in local production of kynurenines, which act through the AHR to impair neutrophil chemotaxis. Indoleamine 2,3-dioxygenase (IDO) is a conserved mammalian metabolic enzyme that catalyzes the first step in tryptophan degradation along the kynurenine pathway. In addition to this role in nutrient utilization, IDO has been implicated in a number of biological processes related to regulation of local immunity such as fetal tolerance, autoimmunity, organ transplantation, and tumorigenesis (1). The immunomodulatory capacity of IDO has been best studied in the context of the adaptive immune response, where induction of this enzyme in dendritic cells restricts the proliferation and survival of T effector cells (1-4). This activity is driven by the breakdown of tryptophan, which both reduces the supply of this essential amino acid available to local T cells and generates an array of bioactive downstream metabolites collectively referred to as kynurenines (1,5,6).Recent studies have identified components of the cellular machinery involved in IDO-dependent responses in lymphocytes. IDO-mediated degradation of tryptophan promotes T cell apoptosis and suppresses proliferation, in part because tryptophan starvation activates the GCN2 pathway, which responds to amino acid insufficiency by initiating a stress response that results in general repression of translation (7,8). The details of how activation of this stress-response pathway alters the T cell activation program are not fully elucidated but likely involve translational regulation of cell cy...

Urinary Tract Infection: Pathogenesis and Outlook

“…For example, secretion of proteins such as UPEC YbcL can lead to a measurable dampening of neutrophil infiltration into the bladder [55–57]. Further, UPEC induces host expression of genes such as IDO , which, via generation of kynurenine metabolites, can cause decreased neutrophil migration across infected bladder epithelia, as evidenced from in vitro Transwell systems, as well as in mice [58, 59]. Some UPEC strains, such as CFT073, can also disrupt host signaling by producing TIR domain-containing proteins such as TcpC; this virulence factor interacts with the host adaptor MyD88 to disrupt TLR4 signaling, while also reducing urinary IL-1β in mice and inhibiting the NLRP3 inflammasome in macrophages [60, 61].…”

Inhibition of antigen-specific immune responses by co-application of an indoleamine 2,3-dioxygenase (IDO)-encoding vector requires antigen transgene expression focused on dendritic cells

“…In our model, CD4 + and CD8 + T cells were shown to cooperate to induce maximal neutrophilic infiltration (Stein et al 2014). The finding that infiltration of neutrophils was significantly suppressed by co-application of pCMV-IDO following βGal protein sensitization suggests that IDO (over)expression in transfected DCs may, on the one hand, via release of kynurenins, directly inhibit neutrophil migration and thereby their lung infiltration (Loughman et al 2016). On the other hand, a tryptophan-depleted and kynurenine-rich micromilieu may affect the viability and migratory activity of antigenspecific T cells that engage antigen-presenting DC.…”

“…Diminished T-cell activation would also impair chemokine production and concomitantly impair neutrophil attraction (Guida and Riccio 2019). In addition, kynurenins were reported to directly inhibit transendothelial migration of neutrophils (Loughman et al 2016).…”

Environmental cues received during development shape dendritic cell responses later in life

“…In other studies, in vivo DC migration from the lung to the MLN during IAV infection was reduced upon AHR activation [ 35 ]. AHR signaling also affects neutrophil trafficking, although it may do so indirectly, via signaling in non-hematopoietic cells, and the direction of change depends upon the stimuli [ 30 , 78 – 81 ]. Also, although AHR signaling affects neutrophil recruitment, it does not affect the number of neutrophils in peripheral tissues in the absence of antigen challenge [ 78 – 80 ].…”