Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis

Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in...

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Bibliographic Details
Published in:JCI insight 2024-02, Vol.9 (5)
Main Authors: Ghatpande, Niraj, Harrer, Aileen, Azoulay-Botzer, Bar, Guttmann-Raviv, Noga, Bhushan, Sudhanshu, Meinhardt, Andreas, Meyron-Holtz, Esther G
Format: Article
Language:English
Subjects:
Animals
Humans
Inflammation
Iron - metabolism
Iron Regulatory Protein 1 - genetics
Iron Regulatory Protein 1 - metabolism
Iron Regulatory Protein 2 - genetics
Iron Regulatory Protein 2 - metabolism
Male
Mice
Orchitis - microbiology
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Summary:Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins 1 and 2 (IRP1 and -2) and these factors are reported to play a role in testicular and immune cell function; however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in less testicular damage and a reduced immune response. Compared with infected wild-type (WT) mice, testes of UPEC-infected Irp1-/- mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast with WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testes of Irp1-/- mice upon UPEC infection. Interestingly, in Irp1-/- UPEC-infected testes, we observed an increase in a subpopulation of macrophages (F4/80+CD206+) associated with antiinflammatory and wound-healing activities compared with WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.175845