4.2.3. Macrophage Origin

There are three main cell groups present in peripheral blood, in other words, the blood circulating throughout the body. Erythrocytes and thrombocytes, which are anucleated cells, and leukocytes (or white blood cells), which are nucleated cells that have a role in immunity. Among leukocytes, two subdivisions exist. The first includes granulocytes (including neutrophils, eosinophils, and basophils), which have the particularity of having a multilobed (polynuclear) nucleus, while the second subdivision includes peripheral blood mononuclear cells (PBMCs).

PBMCs include lymphocytes (T, B, and NK), dendritic cells, and monocytes [162]. These circulating monocytes arise from bone marrow, then migrate into tissues through blood and thanks to local signals (essentially cytokines) differentiate into macrophages [163]. These cells, known as tissue-resident macrophages, have a very long lifespan ranging from a few months to years [164]. Tissue-resident macrophages remain in tissues and contribute to their proper functioning (tissue surveillance and clearing) [165].

Furthermore, the differentiation of monocytes into macrophages takes place in two successive steps. First, in a process called maturation, monocytes transform into naïve macrophages (also called M0). Then, in a second step, these cells could be activated and polarized towards a phenotype (M1 or M2) depending on environmental signals [166]. In some organs, such as the gut, the origin and renewal of tissue-resident macrophages rely exclusively upon circulating monocytes [167]. However, the origin and renewal of resident macrophages from other tissues, such as the brain, liver, or lung, is through embryonic precursors produced either by the yolk sac or by the fetal liver. These precursors act as stem cells by ensuring the renewal of these macrophage populations throughout life [168,169].

In tumors, despite there being widespread recognition that TAMs derive predominantly from circulating monocytes, some studies based on murine models of brain, lung, and pancreatic cancers showed that a significant part of TAMs also derived from tissueresident macrophages [147].
