Biology subjects

Meyron-Holtz, E. G.

Publications and source records attributed to Meyron-Holtz, E. G..

3 recordsLinked to original sources

bioRxiv2023

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

Acute bacterial orchitis (AO) is a prevalent cause of intra-scrotal 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 (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-infected Irp1-/- 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 and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testis of Irp1-/- mice upon UPEC-infection. Interestingly, in Irp1-/- 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.

immunology↗

bioRxiv2022

Aging-related iron deposit prevents the benefits of HRT from late postmenopausal atherosclerosis

Postmenopausal atherosclerosis has been attributed to estrogen deficiency. The beneficial effect of hormone replacement therapy (HRT), however, is lost in late postmenopausal women with atherogenesis. We asked whether aging-related iron accumulation affects estrogen receptor (ER) expression explaining HRT inefficacy. A negative correlation between aging-related systemic iron deposition and ER expression in postmenopausal AS patients was established. In an ovariectomized ApoE-/- mouse model, estradiol treatment had contrasting effects on ER expression in early versus late postmenopausal mice. ER expression was inhibited by iron treatment in cell culture and iron-overloaded mice. Combined treatment with estradiol and iron further decreased ER expression, mediated by iron-regulated E3 ligase Mdm2. In line with these observations, cellular cholesterol efflux was reduced and endothelial homeostasis was disrupted and, consequently, atherosclerosis was aggravated. Accordingly, systemic iron chelation attenuated estradiol-triggered progressive atherosclerosis in late postmenopausal mice. Thus, iron and estradiol together downregulate ER through Mdm2-mediated proteolysis, explaining failures of HRT in late postmenopausal subjects with aging-related iron accumulation. HRT is recommended immediately after menopause along with appropriate iron chelation to protect from atherosclerosis.

cell biology↗

bioRxiv2019

Impaired lysosomal acidification triggers iron deficiency, necrotic cell death and inflammation in vivo

Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain unknown. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and necrotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking lysosomal dysfunction, mitochondrial malfunction and inflammation in vivo.

cell biology↗