Iron in infection and immunity.

The 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.

The immune response to infection in the bladder.

Hepcidin is emerging as a new important factor in brain iron homeostasis. Studies suggest that there are two sources of hepcidin in the brain; one is local and the other comes from the circulation. Little is known about the molecular mediators of local hepcidin expression, but inflammation and iron-load have been shown to induce hepcidin expression in the brain. The most important source of hepcidin in the brain are glial cells. Role of hepcidin in brain functions has been observed during neuronal iron-load and brain hemorrhage, where secretion of abundant hepcidin is related with the severity of brain damage. This damage can be reversed by blocking systemic and local hepcidin secretion. Studies have yet to unveil its role in other brain conditions, but the rationale exists, since these conditions are characterized by overexpression of the factors that stimulate brain hepcidin expression, such as inflammation, hypoxia and iron-overload.

/pdf/hepcidin-an-emerging-and-important-player-in-brain-iron-1t1reft34k.pdf

Hepcidin, an emerging and important player in brain iron homeostasis

Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection.

Urinary hepcidin may have protective effects against AKI. However, renal handling and the potential protective mechanisms of hepcidin are not fully understood. By measuring hepcidin levels in plasma and urine using mass spectrometry and the kidney using immunohistochemistry after intraperitoneal administration of human hepcidin-25 (hhep25) in C57Bl/6N mice, we showed that circulating hepcidin is filtered by the glomerulus and degraded to smaller isoforms detected in urine but not plasma. Moreover, hepcidin colocalized with the endocytic receptor megalin in proximal tubules, and compared with wild-type mice, megalin-deficient mice showed higher urinary excretion of injected hhep25 and no hepcidin staining in proximal tubules that lack megalin. This indicates that hepcidin is reaborbed in the proximal tubules by megalin dependent endocytosis. Administration of hhep25 concomitant with or 4 hours after a single intravenous dose of hemoglobin abolished hemoglobin-induced upregulation of urinary kidney injury markers (NGAL and KIM-1) and renal Interleukin-6 and Ngal mRNA observed 24 hours after administration but did not affect renal ferroportin expression at this point. Notably, coadministration of hhep25 and hemoglobin but not administration of either alone greatly increased renal mRNA expression of hepcidin-encoding Hamp1 and hepcidin staining in distal tubules. These findings suggest a role for locally synthesized hepcidin in renal protection. Our observations did not support a role for ferroportin in hhep25-mediated protection against hemoglobin-induced early injury, but other mechanisms of cellular iron handling may be involved. In conclusion, our data suggest that both systemically delivered and locally produced hepcidin protect against hemoglobin-induced AKI.

/pdf/renal-handling-of-circulating-and-renal-synthesized-hepcidin-58ddn1042v.pdf

Renal Handling of Circulating and Renal-Synthesized Hepcidin and Its Protective Effects against Hemoglobin-Mediated Kidney Injury.

The iron-regulatory peptide hepcidin exhibits antimicrobial activity. Having previously shown hepcidin expression in the kidney, we addressed its role in urinary tract infection (UTI), which remains largely unknown. Experimental UTI was induced in wild-type (WT) and hepcidin-knockout (Hepc-/-) mice using the uropathogenic Escherichia coli CFT073 strain. Compared with infected WT mice, infected Hepc-/- mice showed a dramatic increase in renal bacterial load. Moreover, bacterial invasion was significantly dampened by the pretreatment of WT mice with hepcidin. Infected Hepc-/- mice exhibited decreased iron accumulation in the renal medulla and significant attenuation of the renal inflammatory response. Notably, we demonstrated in vitro bacteriostatic activity of hepcidin against CFT073. Furthermore, CFT073 repressed renal hepcidin, both in vivo and in cultured renal cells, and reduced phosphorylation of SMAD kinase in vivo, suggesting a bacterial strategy to escape the antimicrobial activities of hepcidin. In conclusion, we provide new mechanisms by which hepcidin contributes to renal host defense and suggest that targeting hepcidin offers a strategy to prevent bacterial invasion.

/pdf/hepcidin-as-a-major-component-of-renal-antibacterial-12m3drh3pt.pdf

Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli

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Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli