One of the macrophage subtypes that has attracted attention in recent years is the Mhem macrophage, which is induced by hemoglobin-haptoglobin (Hb-Hp) complexes in atherosclerotic plaques. Mhem macrophages express high levels of CD163, a scavenger receptor for Hb-Hp complexes, and heme oxygenase-1 (HO-1), an enzyme that degrades heme into biliverdin, carbon monoxide, and iron. Mhem macrophages also produce anti-inflammatory cytokines such as interleukin-10 (IL-10) and signal transducer and activator of transcription 3 (STAT3).

Mhem macrophages have been proposed to have beneficial effects on atherosclerosis by reducing oxidative stress, inflammation, and lipid accumulation in plaques. However, the exact role and regulation of Mhem macrophages in atherosclerosis are still unclear and controversial. Moreover, the therapeutic potential and challenges of targeting Mhem macrophages for atherosclerosis treatment remain to be explored.

Creative Biolabs summarizes the current knowledge and perspectives on Mhem macrophages in atherosclerosis, focusing on their phenotypic diversity, functional plasticity, role in disease development and progression, and therapeutic implications.

Phenotypic Diversity and Functional Plasticity of Mhem Macrophage

In atherosclerosis, macrophages can be classified into several subtypes based on macrophage markers and functional properties, such as M1, M2, Mox, and M4.

Fig.1 In atherosclerotic plaques, macrophages differentiate into different subtypes according to the vascular microenvironment.¹

Mhem macrophages are a subtype of macrophages that are induced by Hb-Hp complexes in atherosclerotic plaques. They express high levels of CD163, HO-1, IL-10, and STAT3. Mhem macrophages have been suggested to have a protective role in atherosclerosis by reducing oxidative stress, inflammation, and lipid accumulation in plaques. However, the phenotypic diversity and functional plasticity of Mhem macrophages are not fixed or stable, but rather depend on the dynamic microenvironment of atherosclerotic plaques.

• Mhem macrophages can switch to a pro-inflammatory phenotype when exposed to lipopolysaccharide (LPS) or interferon-gamma (IFN-γ).
• Mhem macrophages can switch to an oxidative stress-responsive phenotype when exposed to oxidized low-density lipoprotein (oxLDL) or iron.

Moreover, Mhem macrophages can also co-express markers of other macrophage phenotypes, such as iNOS, Arg-1, MCPIP1, or CCR2. Therefore, the phenotypic diversity and functional plasticity of Mhem macrophages reflect their adaptability and complexity in response to the changing microenvironment of atherosclerotic plaques.

Role of Mhem Macrophages in Atherosclerosis Development and Progression

Mhem macrophages are not only phenotypically diverse and functionally plastic, but also play a crucial role in the development and progression of atherosclerosis. Mhem macrophages have been shown to exert both beneficial and detrimental effects on plaque inflammation, lipid metabolism, vascular remodeling, and immune modulation, depending on the context and stage of the disease.

• Mhem macrophages have been reported to have anti-inflammatory and anti-oxidative effects on atherosclerotic plaques.
  • Mhem macrophages can scavenge Hb-Hp complexes and degrade heme via CD163 and HO-1, respectively, thereby reducing the oxidative stress and inflammation induced by free hemoglobin and heme in the plaque microenvironment.
  • Mhem macrophages can also produce IL-10 and activate STAT3, which can inhibit the expression of pro-inflammatory cytokines and suppress the activation of NF-κB and MAPK signaling pathways.
  • Moreover, Mhem macrophages can induce the expression of anti-apoptotic genes and protect plaque cells from oxidative stress-induced apoptosis.
• However, Mhem macrophages can also have adverse effects on plaque stability, lipid metabolism, vascular remodeling, and immune modulation.
  • Mhem macrophages can release iron as a by-product of heme degradation, which can catalyze the formation of reactive oxygen species (ROS) and exacerbate plaque oxidative stress.
  • Mhem macrophages can also accumulate cholesterol esters from Hb-Hp complexes via CD163-mediated endocytosis, and contribute to plaque lipid accumulation and foam cell formation.
  • Furthermore, Mhem macrophages can secrete matrix metalloproteinases (MMPs), which can degrade the extracellular matrix (ECM) and weaken the fibrous cap of the plaque.
  • Additionally, Mhem macrophages can interact with other cell types in atherosclerosis and modulate their functions in various ways.
  • Mhem macrophages can also inhibit smooth muscle cell proliferation and migration by producing TGF-β and prostaglandin E2 (PGE2).
  • Mhem macrophages can also regulate T cell polarization and activation by expressing MHC-II molecules and co-stimulatory molecules.
  • Mhem macrophages can also influence platelet aggregation and thrombosis by releasing thromboxane A2 (TXA2) and platelet-activating factor (PAF).

Therefore, the role of Mhem macrophages in atherosclerosis development and progression is complex and context-dependent. Mhem macrophages may have a protective role in the early stages of atherosclerosis by reducing plaque inflammation and oxidative stress, but may have a detrimental role in the advanced stages of atherosclerosis by compromising plaque stability, enhancing lipid accumulation, impairing vascular remodeling, and modulating immune responses.

Therapeutic Implications and Future Perspectives of Mhem Macrophages in Atherosclerosis

Mhem macrophages are not only important for understanding the pathophysiology of atherosclerosis, but also for developing novel and effective therapies for atherosclerosis. Mhem macrophages have been proposed as potential targets or vehicles for atherosclerosis treatment.

• To modulate their phenotype and function by using pharmacological or genetic approaches.
  • Some drugs such as statins, aspirin, or curcumin can enhance the expression of CD163 and HO-1 in Mhem macrophages, and increase their anti-inflammatory and anti-oxidative effects on plaques.
  • Some genes such as HO-1, IL-10, or STAT3 can be overexpressed or silenced in Mhem macrophages by using viral vectors or macrophage-targeted nanoparticles, and alter their phenotypic and functional properties.
• To enhance their clearance or removal from plaques by using immunological or physical methods.
  • Some antibodies such as anti-CD163 or anti-HO-1 can bind to Mhem macrophages and induce their phagocytosis by other immune cells or their apoptosis by activating caspases.
  • Some devices such as ultrasound or magnetic resonance imaging (MRI) can generate mechanical forces or thermal energy that can disrupt or destroy Mhem macrophages in plaques.
• To use them as vehicles or carriers for delivering drugs or genes to plaques by exploiting their natural tropism and accumulation in plaques.
  • Some drugs such as rapamycin or paclitaxel can be loaded into nanoparticles that are coated with Hb-Hp complexes or CD163 ligands, and then administered intravenously to target Mhem macrophages in plaques.
  • Some genes such as p53 or caspase-3 can be inserted into viral vectors that are modified with Hb-Hp complexes or CD163 ligands, and then injected intravenously to transfect Mhem macrophages in plaques.

Therefore, targeting Mhem macrophages for atherosclerosis therapy is a promising but challenging field of research. There are many opportunities and possibilities for exploiting the therapeutic potential of Mhem macrophages in atherosclerosis.

Reference

1. Li, Hongxia, et al. "Macrophage subsets and death are responsible for atherosclerotic plaque formation." Frontiers in Immunology 13 (2022): 843712.