MFe^hi adipose tissue macrophages compensate for tissue iron perturbations in mice

Area of Science:

• Adipose tissue biology
• Immunometabolism
• Macrophage biology

Background:

• Resident adipose tissue macrophages (ATMs) maintain tissue homeostasis and regulate metabolic functions.
• Macrophages possess phagocytic and oxidative resilient properties, enabling roles in innate immunity and tissue-specific needs like iron homeostasis.
• A recently identified subtype, MFehi ATMs, exhibit elevated intracellular iron and express iron-handling genes, suggesting a role in adipose tissue iron regulation.

Purpose of the Study:

• To investigate the response of MFehi ATMs to iron overload conditions.
• To determine how MFehi ATMs influence adipose tissue iron availability and adipocyte health.
• To characterize the cellular mechanisms and inflammatory profile of MFehi ATMs during iron excess.

Main Methods:

• Utilized dietary iron supplementation to induce chronic iron excess.
• Employed intraperitoneal iron injection to model acute iron overload.
• Quantified intracellular iron content in ATMs and adipocytes using specific methodologies.
• Analyzed gene expression related to iron storage and inflammatory markers in ATMs.

Main Results:

• MFehi ATMs accumulated excess iron in response to high dietary iron, while MFelo ATMs and adipocytes did not.
• In chronic iron excess, MFehi ATMs showed increased expression of iron storage genes.
• Following acute iron injection, MFehi ATMs incorporated high iron levels, sparing adipocytes from overload.
• Acute iron overload led to an increase in MFehi ATMs, primarily through MFelo ATM conversion, without altering their low inflammatory profile.

Conclusions:

• MFehi ATMs function as a significant iron sink in adipose tissue, protecting adipocytes from iron overload.
• Adipose tissue macrophages can adapt to iron excess by increasing iron storage and cellularity.
• The MFehi ATM population maintains a non-inflammatory phenotype even under conditions of iron accumulation.