Introduction to Macrophages

The discovery of macrophages dates back to 1882, when biologist Ellie Metchnikoff discovered them while studying primitive animals that lacked adaptive immune mechanisms and referred to these cells as phagocytes. Macrophages are a heterogeneous group of immune cells with a high degree of plasticity and a variety of functions, including tissue development and homeostasis in vivo, removal of cellular debris, elimination of pathogens, and modulation of inflammatory responses. Different inducing signals can activate macrophages to alter their own morphology and physiological characteristics.

Fig 1 macrophage origin

Borrowing the concept of helper T cells (Th), the macrophage activation state is usually simplified in terms of activation modality into two categories: classically activated macrophages, CAMs, and alternatively activated macrophages, AAMs. M1 macrophages produce pro-inflammatory cytokines, which resist pathogen invasion but also cause organismal damage; M2 macrophages secrete anti-inflammatory cytokines and play a role in tissue repair and reconstruction and tumor formation.

Fig 2 Different phenotypes, cell surface markers and functions of macrophages

It is worth noting that the two macrophage phenotypes are not absolutely antagonistically differentiated, i.e., the M1 and M2 phenotypes are not mutually exclusive but often coexist, and thus cannot simply be considered to be completely distinct macrophage populations. Macrophage polarization markers are usually expressed at different levels on macrophages of different phenotypes, and macrophages of different phenotypes can undergo interconversion under certain conditions. In wound healing in vivo, macrophages exhibit a pro-inflammatory M1 secretion profile in the early phase, with a high capacity to present antigens and produce interleukins IL-12 and IL-23, which inhibit cell proliferation and cause tissue damage, while in the late healing phase, macrophages shift to an anti-inflammatory M2 gene expression profile, which promotes inflammation and wound healing through the production of angiogenic mediators, such as TGF-β, VEGF, and EGF, and so on. subside and wound healing. 

Fig 3 Mechanisms of major macrophage activation phenotypes in tissue repair, regeneration, and fibrosis

In vivo study

Macrophages are the only cells present in every organ in the body and are found in the epidermis, cornea, and the interior of joints without blood vessels, and one of the most important methods of studying their in vivo biology is macrophage depletion. In vivo macrophage depletion is a method of removing macrophages using physicochemical or genetic techniques. This method is now widely used to study the role of macrophages in animal disease models and to study the mechanisms of immunopathology or inflammatory damage, such as inflammatory diseases: allergic asthma, diabetes, obesity, atherosclerosis, autoimmune disease-related studies; and other areas of disease: tumors, viral-associated diseases, tissue regeneration, and other related studies. The clodronate liposome method is currently the most commonly used method for macrophage depletion.

Clodronate Liposomes

Since Prof. Nico van Rooijen successfully developed a Clodronate Liposomes in vivo situation cell removal agent by utilizing the macrophage endocytosis mechanism to bring clodronate into the cell, where chlorophosphoric acid is released, which can trigger macrophage apoptosis when a certain concentration is reached, thus achieving the purpose of macrophage removal. This reagent has been widely used as the most mature and convenient macrophage removal tool in the world.

Fig 4 Schematic diagram of macrophage clearance principle

Approaches of different organizations (for information only)

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