Inhibition of the scavenger receptor by fucoidan reduces mitochondrial H2O2production, which inhibits macrophage M2 polarization [88]. metabolic switches can facilitate the development of targeted therapies for various diseases. Keywords: Macrophage, Macrophage polarization, Alternative activation, Pulmonary fibrosis, Mitochondria, Reactive oxygen species, Fatty acid oxidation == Origins of Macrophages == Macrophages are innate immune cells of the mononuclear phagocyte system that play an important role in the cross-talk between the innate and adaptive immunity [1, 2]. The function of macrophages varies significantly with regard to tissue specificity, such as the back macrophages, the adipose tissue macrophages, Kupffer cells in the liver, and microglia cells in the central nerve system. Based on the expression of F4/80, murine tissue macrophages can trace their origin back to two sources. Macrophages that are derived within bone marrow usually express low F4/80, whereas macrophages that originate from the embryonal yolk sac typically express high level of F4/80 and are capable of proliferatingin situ, a scenario seen in the radiation-induced chimeras and the bone marrow transplant mice [35]. To further delineate the circulating monocyte derived macrophages, studies using specific surface markers, lymphocyte antigen 6C (Ly6C), C-C chemokine receptor type 2 (CCR2), and CX3C chemokine receptor 1 (CX3CR1), two sets of monocytes are identified: the Ly6C-highand Ly6C-lowmonocytes [6]. The Ly6Chighmonocytes are inflammatory monocytes, which have high expression L-NIO dihydrochloride of CCR2 and a low level of CX3CR1. They are short-lived and rapidly recruited L-NIO dihydrochloride to the site of inflammation during the acute infectious process. The Ly6Clowmonocytes do not express CCR2 but have high level of CX3CR1. They usually do not migrate immediately to the site of infection due to their low expression of CCR2. However , Ly6Clowmonocytes are usually long-lived cells and play an important role in chronic processes, such as tumorigenesis and fibrotic remodeling. == Macrophage Polarization == Macrophage polarization is a process through which macrophages obtain different phenotypes. The phenotype of a macrophage is closely related to the microenvironment in which they reside, as macrophages are able to switch phenotypes constantly bothin vivoandin vitro[7, 8]. In an analogy to the T-helper-cell nomenclature, where Th1 cells are associated with the response against bacteria or viruses, and Th2 cells are associated with the response to parasitic infection and tissue remodeling, macrophages can be denoted as M1 and M2 macrophages. M1 macrophages (or classically activated macrophages, CAMs) are L-NIO dihydrochloride pro-inflammatory and have potent microbicidal and tumoricidal activity, whereas the M2 macrophages (or alternatively activated macrophages, AAMs) are involved in tumor progression and tissue remodeling, including fibrosis [9, 10]. Classical macrophage activation requires priming with IFN-, the canonical cytokine generated by Th1 cells, and activation of the downstream transcription factors, such as signal transducer and activator of transcription 1 (STAT1), nuclear factor-kappa lightchain-enhancer of activated-B cells (NF-B), and interferon regulatory factor 5 (IRF-5). These M1 macrophages express L-NIO dihydrochloride inflammatory genes, including TNF-, IL-1, and IL-6. Alternatively activated macrophages are usually activated by Th2 cytokines, IL-4 and/or IL-13. The wide range of immunosuppressive cytokines and growth factors alternatively activated macrophages Tek produce, such IL-10, IL-1ra (IL-1 receptor antagonist), and transforming growth factor- (TGF-), are closely related to their ability to attenuate inflammation and promote extracellular tissue remodeling. Transcription factors involved in M2 polarization include STAT3, STAT6, IRF-4, and peroxisome proliferator-activated receptor (PPAR)- (Figure 1). Differential metabolism of L-arginine is characteristic of M1 and M2 macrophages. L-arginine is metabolized by iNOS to generate nitric oxide (NO) in M1 macrophages and by arginase-1 in M2 macrophages to augment the production of polyamines and L-proline, which are essential substrates for collagen synthesis [11, 12]. == Determine 1 . == General concepts of macrophage polarization and properties of M1 and M2 macrophages. INF- induces M1 (classical) macrophage polarization whereas IL-4 and/or IL-13 induce M2 (alternative) macrophage polarization. The origin of macrophages also plays a critical role in determining macrophage phenotype. L. sigmodontisinfection induces M2 macrophage proliferationin situ, rather than by the recruitment and differentiation of L-NIO dihydrochloride circulating monocytes [13]. In contrast, in a LPS-induced COPD model, using MRI tracking of nanoparticles-labeledex festn, prepolarized bone marrow-derived macrophages, both M1 and M2 are recruited to the sites of inflammation in the lung at similar level [14]. == Macrophage polarization and human diseases == The classically activated M1 macrophages boast the basic macrophage function as implied by the name given by Elie Metchnikoff in 1887. They are the dominant cells in acute infection, participating in bacteria/pathogen clearance and antigen presenting by their effective phagocytic ability. They also have compelling tumoricidal activity. M2 macrophages are actively involved in many processes associated.
Inhibition of the scavenger receptor by fucoidan reduces mitochondrial H2O2production, which inhibits macrophage M2 polarization [88]