Macrophagic control of the response to uropathogenic E. coli infection by regulation of iron retention in an IL‐6‐dependent manner

Abstract

IntroductionUropathogenic Escherichia coli (UPEC), the causative agent of over 85% of urinary tract infections (UTIs), elaborate a number of siderophores to chelate iron from the host. On the other hand, the host immune imperative is to limit the availability of iron to the bacteria. Little is known regarding the mechanisms underlying this host‐iron‐UPEC interaction. Our objective was to determine whether macrophages, in response to UPEC infection, retain extracellular siderophore‐bound and free iron, thus limiting the ability of UPEC to access iron.MethodsQuantitative PCR, immunoblotting analysis, and gene expression analysis of wild type and IL‐6‐deficient macrophages was performed.ResultsWe found that (1) macrophages upon UPEC infection increased expression of lipocalin 2, a siderophore‐binding molecule, of Dmt1, a molecule that facilitates macrophage uptake of free iron, and of the intracellular iron cargo molecule ferritin, and decreased expression of the iron exporter ferroportin; (2) bladder macrophages regulate expression of genes involved in iron retention upon UPEC infection; (3) IL‐6, a cytokine known to play an important role in regulating host iron homeostasis as well as host defense to UPEC, regulates this process, in part by promoting production of lipocalin 2; and finally, (4) inhibition of IL‐6 signaling genetically and by neutralizing antibodies against the IL‐6 receptor, promoted intra‐macrophagic UPEC growth in the presence of excess iron.ConclusionsTogether, our study suggests that macrophages retain siderophore‐bound and free iron in response to UPEC and IL‐6 signaling is necessary for macrophages to limit the growth of UPEC in the presence of excess iron. IL‐6 signaling and iron regulation is one mechanism by which macrophages may mediate UPEC clearance.

Bladder resident macrophages: Mucosal sentinels

“…Additional time points, uptake and degradation studies, and in vivo experiments are needed to determine whether UPEC can truly persist inside macrophages. It is noteworthy that only one study has investigated UPEC infection using macrophages isolated from the bladder [58]. In this study, macrophages isolated from mouse bladders upregulate iron sequestering molecules, thereby likely limiting iron availability for UPEC and inhibiting growth in the bladder [58].…”

“…It is noteworthy that only one study has investigated UPEC infection using macrophages isolated from the bladder [58]. In this study, macrophages isolated from mouse bladders upregulate iron sequestering molecules, thereby likely limiting iron availability for UPEC and inhibiting growth in the bladder [58]. By contrast, the vast majority of in vitro studies investigating macrophage-UPEC interactions rely upon monocyte-derived or peritoneal macrophages.…”

Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder

“…Recently, uptake of UPEC in an ATG16L1-dependent manner 13 and iron retention by macrophages in the urinary bladder have been observed. 11,12 Our study demonstrates that relocated macrophages in the urothelium phagocytose UPEC to reduce infection. Hence, this process of phagocytosis of UPEC is an important antimicrobial mechanism during acute infections of the urinary bladder.…”

“…[5][6][7] The absence of macrophages impeded the response against UPEC. [8][9][10] Furthermore, there is emerging evidence that macrophages retain free iron to limit UPEC growth 11 and also phagocytose UPEC directly in an ATG16L1-dependent manner. 12,13 However, the molecular mechanism which regulates the spatial distribution of macrophages within the urothelium upon UPEC infection has not been studied so far.…”

Murine SIGNR1 (CD209b) Contributes to the Clearance of Uropathogenic Escherichia coli During Urinary Tract Infections

“…Hosts can counteract invading bacterial pathogens utilizing their defensive weapons of APCs, including DCs and macrophages. The interactions between host macrophages and uropathogens are considered crucial to initiate an efficient immune response that defends against invading bacteria in UTIs (Mora-Bau et al, 2015;Owusu-Boaitey et al, 2016;Lacerda Mariano and Ingersoll, 2018).…”