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

Abstract

AbstractAcute bacterial orchitis (AO) is a prevalent cause of intra-scrotal inflammation, often resulting in sub-or infertility. A frequent cause eliciting AO is uropathogenicEscherichia 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 (IRP) 1 and 2 and these factors have been reported to play a role in testicular and immune cell function, however, their precise role remains unclear. Here, we show in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in reduced immune response and testicular damage. Compared to infected wild-type (WT)-mice, testis of UPEC-infectedIrp1-/-mice showed impaired ERK signalling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast to WT andIrp2-/-mice, no increase in monocytes and neutrophils was detected in testis ofIrp1-/-mice upon UPEC-infection. Interestingly, inIrp1-/-UPEC-infected testis, we observed an increase in a subpopulation of macrophages (F4/80+ CD206+) associated with anti-inflammatory and wound-healing activities compared to WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signalling and dampening the immune response.