Macrophages During the Fibrotic Process: M2 as Friend and Foe

Abstract

Macrophages play essential activities in homeostasis maintenance during different organism's conditions. They may be polarized according to various stimuli, which subsequently subdivide them into distinct populations. Macrophages with inflammatory activity function mainly during pathological context, while those with regulatory activity control inflammation and also remodel the repairing process. Here, we propose to review and to present a concise discuss on the role of different components during tissue repair, including those related to innate immune receptors and metabolic modifications. The scar formation is directly related to the degree of inflammation, but also with the appearance of M2 macrophages. In spite of greater numbers of macrophages in the fibrotic phase, regulatory macrophages present some characteristics related to promotion of fibrosis but also with the control of scar formation. These regulatory macrophages present an oxidative metabolism, and differ from the initial inflammatory macrophages, which in turn, present a glycolytic characteristic, which allow regulatory ones to optimize the oxygen consumption and minimizing their ROS production. We will emphasize the difference in macrophage subpopulations and the origin and plasticity of these cells during fibrotic processes.

Keywords: cell metabolism; fibrosis; macrophage activation; myofibroblasts; polarization.

Figure 1

Macrophages are present in all mammalian tissues, contributing to homeostasis and organ disease. Most tissue macrophages have an embryonic origin, and they are not fully derived from circulating monocytes. From embryonic day 6.5–8.5, resident macrophages can be generated in yolk sac. These macrophages can be identified as being regulated by CSF1R, and they are independent of the factor myb. Subsequently, during day E 8.5 to E 10.5 hematopoietic stem cells (HSCs)-derived aorta-gonad-mesonephros can migrate to fetal liver and establish a temporary hematopoiesis, giving rise, for example, to Langerhans cells and alveolar macrophages. In addition, resident macrophages derived from fetal liver may originate both HSCs precursors and mature erythro-myeloid cells. Finally, during the perinatal period, HSCs migrate to the bone marrow to establish itself a definitive place of hematopoiesis that will last until the adulthood. On this point, they are produced as Ly6C⁺CCR2^high and Ly6C⁻CX3CR1^high monocytes capable of infiltrating organs and differentiate into macrophages. Both infiltrating and residents macrophages can be polarized to M1 and M2 according to the microenvironment stimuli.

Figure 2

Participation of M1 and M2 macrophages in the process of fibrosis. The activation of myofibroblasts is a physiological process generated in order to repair and restore tissue homeostasis. However, if the insult persists, fibrosis progress with proliferation of myofibroblasts and deposition of ECM which replaces functional tissue, leading to scar tissue formation. In this context, M1 macrophages represent the starting point of pro-fibrotic process. Therefore, M1 releases pro-inflammatory cytokines and chemokines that indirectly promote the proliferation of myofibroblasts. M1 can release CCL2, assisting in the recruitment of fibrocytes and also MMP-9, that promotes EMT/EndoMT. M1 has also been associated with an anti-fibrotic effect by releasing MMPs that degrade ECM. M2 macrophages can be generated by phagocytosis of apoptotic bodies or Th2 cytokines stimulation. M2 is initially anti-inflammatory cells through the release of IL10, arginase, TGFβ and HO-1. But when the damage persists, M2 activation leads to EMT/EndoMT as well as proliferation of fibrocytes due to the release of several growth factors. In this sense, macrophage modulation is the central axis of the exacerbation or control of fibrosis.