**2. Macrophages and their role in inflammation**

Neutrophils, macrophages and other cells involved in the innate immune system constitute a first line of defense against microorganisms and are critical for the control and resolution of common infections [16]. However, not all infectious organisms can be recognized by macrophages, for which lymphocytes of the adaptive immune system are present to create a more versatile defense system [17]. The innate and adaptive immune systems cooperate through many interactions among different cell types. For example, cells of the innate immune system such as macrophages, dendritic cells and natural killer (NK) cells orchestrate the initiation and the subsequent progression of lymphocyte-mediated adaptive immune responses, and then receive feedback signaling from lymphocytes to adapt their phenotypes and functions for the direct involvement in the removal of pathogens targeted by adaptive immune responses [18]. Moreover, the innate immune response by macrophages is the critical response to control infections before the adaptive immune response takes effect a few days after the infection [19]. Furthermore, macrophages also contribute to directing the adaptive immune response through antigen presentation and production and secretion of cytokines and chemokines [20].

Classical macrophages display a pro-inflammatory phenotype, which has been designated as "M1" macrophages, while another subtype of macrophages that are alternatively differentiated and exhibit anti-inflammatory properties or contribute to resolution of inflammation, tissue regeneration and remodeling, have been designated as "M2" macrophages [21]. The overall M1 or M2 characteristics in a given macrophage is called its "polarization" [22]. When a macrophage changes its expression pattern to fit a more M1 or M2 phenotype, it is called a polarized macrophage [22]. Macrophage polarization can either occur in undifferentiated macrophages (naïve macrophages) or occur in polarized macrophages, which is then called "re-polarization" [22]. It is now known that polarization of macrophages into the precise definition of "M1" or "M2" macrophages rarely occurs. Instead, macrophage typically polarize into a wide spectrum of phenotypes that exhibit distinct gene and protein expression patterns [23]. This broad range of differentiation pattern allows macrophages to perform diverse tasks throughout the body [23]. M1 macrophages are characterized by high levels of proinflammatory markers such as reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), nitric oxide (NO), CD11c, tumor necrosis factor (TNF)α, interleukin (IL)-6, IL-1β and major histocompatibility complex (MHC)-II [24]. In contrast, M2 macrophages express markers associated with healing and inhibition of inflammation such as high levels of arginase 1, CD163, CD206, CD301, IL-10, resistin-like molecule alpha1 (Fizz1) and chitinase-like protein 3 (Ym1) [25]. Microenvironmental autocrine and paracrine signals, together with epigenetic changes, seem to influence macrophage activation and polarization [26].
