They point out the key role of the NOD1 protein in iron-related diseases

An investigation led by the CIBERCV and the Alberto Sols Biomedical Research Institute (CSIC-UAM) describes the pre-eminent role of this protein in iron homeostasis and ferroptosis. The results of this work, published in Biomedicine & Pharmacotherapy , open the door to new lines of research for the diagnosis and treatment of iron-related diseases.

The NOD1 protein, which had already been linked to numerous inflammatory and cardiovascular pathologies, also plays a prominent role in the balance of iron levels in the body (homeostasis) and ferroptosis (cell death due to excess iron). This is demonstrated by a study led by the Cardiovascular Diseases area of the CIBER (CIBERCV) and the Alberto Sols Biomedical Research Institute (CSIC-UAM), with the participation of the CIBER for Liver and Digestive Diseases (CIBEREHD). The work highlights that NOD1-mediated mechanisms could provide new avenues for advancing research in both the diagnosis and treatment of iron-related diseases.

The bioavailability of iron is essential for the proper functioning of various organs and cellular processes. In mammals, oxygen transport is dependent on hemoproteins, but processes such as the regulation of gene transcription or the production of free radicals as defense mechanisms against pathogens are also closely related to iron. The deregulation of iron metabolism leads to various diseases, from different types of anemia to infections, as well as alterations in the immune system, inflammation or even atherosclerosis. Not only does iron deficiency lead to these pathologies, but its excess is also harmful and is the main cause of a specific cell death process known as ferroptosis.

Therefore, the control of iron homeostasis is a key factor for proper cell function. In this sense, monocytes and macrophages are essential in the modulation of iron metabolism, as well as the function of the spleen, which is also one of the main organs that regulate its bioavailability.

The objective of this new work focused on studying the role of an immune system protein, NOD1, which had previously been linked to numerous disorders, including certain inflammatory and cardiovascular diseases. "The connections between iron metabolism and cardiovascular diseases such as atherosclerosis are still poorly defined," says Lisardo Boscá, group leader of the CIBERCV at the Alberto Sols Biomedical Research Institute and one of the coordinators of this study. Therefore, this team focused on the contribution of NOD1 to the function of monocytes and macrophages for iron homeostasis in an atherogenic context, studying human and mouse models.

Iron homeostasis and atherosclerosis

"Our findings highlight the preeminent role of NOD1 in iron homeostasis and ferroptosis, especially in pro-atherogenic conditions," says Dr. Boscá.

Specifically, this team was able to observe that mice lacking NOD1 and subjected to atherogenic conditions (by administering a high-fat diet) had a marked decrease in iron content in various organs, including the spleen, liver and heart, three of the largest reservoirs and regulatory tissues of this element.

At the same time, it was determined that these organs presented significant fibrosis as a consequence of the increased content of proinflammatory cells from the circulation. "In the absence of NOD1, iron levels decreased in the spleen, and this decrease in iron was accompanied by an increase in macrophage recruitment," explains Victoria Fernández, one of the main authors of the study. "One of the factors involved in this recruitment is the increase in the interleukin 8 receptor, also known as CXCR, which mediates the mobilization (chemotaxis) of monocytes and macrophages to areas of inflammation, including the atherosclerotic plaque," she explains.

In addition, the investigations carried out by this group allowed us to observe that the activation of NOD1 increased the levels of GPX4 and other iron-regulating proteins, leading to less ferroptosis.

"These results open new avenues for the diagnosis and treatment of diseases related to iron and mediated by NOD1", highlight both scientists. In this field, they point out that the connections between ferroptosis, modulation of spleen function, atherosclerosis and leukocyte mobilization provide multidisciplinary fields for research and the identification of new pharmacological targets against different immunometabolic diseases, such as different types of anemias, including sickle cell anemia, among others.

Image: NOD1 activation protects against ferroptosis in macrophages / Fernández-García et al.

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Bibliographic reference:

Fernandez-Garcia, V.; González-Ramos, S.; Avendaño-Ortiz, J.; Martin-Sanz, P.; Slim, C.; Castrillo, A.; Boscá, L. 2022. NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions . Biomedicine & Pharmacotherapy , 148: 112769. doi: 10.1016/j.biopha.2022.112769.