Macrophages are present in nearly all tissues of the human body. These cells, whose foremost function is phagocytosis, are of importance in maintaining steady-state tissue homeostasis [1-3]; macrophages participate in, among others, wound healing, the production of growth factors and removal of apoptotic bodies and cellular debris originating from tissue remodeling [1, 3]; boek the immune system p. 13). Another example of macrophage activity that is favorable to human health, is the metabolic clearance of erythrocytes (± 2 x 1011 each day) enabling the reuse of both iron and hemoglobulin  boek essential cell biology alberts et al. p 524). Additionally to the involvement in tissue homeostasis, macrophages play an indispensable role in immunity such as involvement in the primary response against invading microorganisms, coordination of the adaptive immune response and inflammation [1-2].
Differentiation of macrophages
Macrophages differentiate from circulating monocytes [1, 4]; boek the immune system p. 13). The migration of monocytes from blood to tissue can occur either in steady state or during inflammation [5-7]. Monocytes originate from a common myeloid progenitor in the bone marrow [1, 8-9]. When released from the bone marrow circulating blood monocytes can migrate into virtually all tissues of the body, in response to chemotactic signals such as cytokines, and subsequently differentiate into macrophages [4, 9]. Three different types of macrophages can be indicated after monocyte-to-macrophage differentiation: endothelium-resident macrophages, tissue-resident macrophages, and recruited macrophages [9-10].
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Kupffer cells (liver), Langerhans cells (skin), microglia (central nervous system), and osteoclasts (bone) all belong to tissue-resident macrophage populations that have been adapted to their local microenvironment [9-10]. Several studies have indicated that numerous tissue-resident macrophage populations (i.e. alveolar macrophages, splenic white-pulp and metallophilic macrophages, liver Kupffer cells, and brain microglia) are predominantly sustained trough local proliferation during steady state instead of replenishment by circulating monocytes (Reviewed in ). Conversely, in response to injury or infection, tissue-resident macrophages are locally activated and a fast recruitment of circulatory monocytic precursors into the corresponding infected or inflamed tissue is observed (Reviewed in ) . These macrophages do not only have an increased turnover rate, but also show an altered phenotype . Diverse stimuli from immunological and inflammatory processes may generate different types of recruited macrophages: antigen-non-specific responses may generate 'elicited' macrophages, whereas antigen-specific immune responses contribute to the formation of 'classically activated' and 'alternatively activated' macrophages [9-10]. According to Gordon et al., 2003, 'it is difficult to distinguish between originally resident macrophages from more recently recruited, elicited, or activated macrophages, because cells adapt to a particular microenvironment' . A detailed overview of macrophage differentiation is displayed in Figure 1.
Figure 1â”‚ Monocyte-to-macrophage differentiation . The development of monocytes from a common myeloid progenitor requires the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), which stimulates the proliferation and maturation of these cells. Moreover, interleukin 3 (IL-3), KIT, tumor-necrosis-factor (TNF)-family proteins, TNF-receptor-related molecules, as well as PU.1 initiate the determination of macrophages. Bone-marrow monocytes are released into the peripheral blood from where they can enter virtually all tissues of the body. Monocyte migration through the endothelial layer is controlled by integrins, selectins, immunoglobulin super family molecules, and epidermal growth factor seven-transmembrane spanning (EGF-TM7)-type receptors. In tissues, monocytes may differentiate further into tissue-resident macrophages or recruited macrophages, the latter in response to inflammatory or immune stimuli. Resident-tissue macrophages may develop into different types of cells such as Langerhans cells or osteoclasts, dependent on signals from their local microenvironment (i.e. surface and secretory products of neighboring cells, and extracellular matrix). Tissue-resident macrophages that do not die in situ may migrate into draining lymph nodes after which they are filtered from the afferent lymph. Additionally, tissue-resident macrophages can enter the circulatory system again and consequently differentiate into dendritic cells (DCs).
Classically and alternatively activated macrophages
As mentioned, classically and alternatively activated macrophages are both formed in response to antigen-specific immunity. However, as a result of their extensive plasticity, macrophages may express phenotypic alterations in response to diverse environmental signals by which dissimilar (functional) populations of macrophages are formed ; different microbial stimuli and cytokines contribute to the formation of either classically or alternatively activated macrophages [9, 11-12]. Apart from cytokines such as GM-CSF and tumor-necrosis factor (TNF) and microbial products like lipopolysaccharide (LPS), IFN-É£ is considered as the predominant inducer of classically activated macrophages [12-14]. Alternatively activated macrophages can be formed in response to anti-inflammatory molecules such as IL-4, IL-13 or IL-10, immune complexes, vitamin D3, and glucocorticoid hormones [11, 15-16].
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Related to the Th1/Th2 nomenclature, classically activated and alternatively activated macrophages can be categorized as M1 and M2 macrophages respectively [1, 11, 13-14]. In total, three different sub-forms of M2 macrophages can be identified, each expressing a characteristic set of cytokines and cell surface markers: M2a, M2b, M2c (Figure 2).
Besides their contribution to Il-12 mediated Th1 responses, M1 macrophages are able of killing intracellular pathogens and tumor cells [11-13]. Additionally, M1 macrophages can produce numerous amounts of pro-inflammatory cytokines such as IL-12, Il-1β and TNF . M2 macrophages on the other hand, are involved in Th2-type inflammatory processes, allergy, tumor promotion, killing and encapsulation of parasites, and tissue remodeling and repair . The activation of M2 macrophages is accompanied by a reduction in pro-inflammatory cytokine production compared to M1 macrophage activation; M2 macrophages predominantly produce anti-inflammatory cytokines such as Il-10 and IL-1 receptor antagonist (Il-1ra). In addition to the dissimilar patterns of cytokine production, both types of macrophages express different phenotypically characteristics, receptors as well as effector functions (Figure 2) [11, 15, 17]. For instance, M1 macrophages are hallmarked by an IL-10low, IL-12high, Il-23high phenotype [11-13]. Conversely, a phenotype comprising IL-10high, IL-12low, and IL-23low is characteristic for M2 polarized macrophages [11, 13]). M1 macrophages express opsonic receptors (e.g. FcÉ£RIII), whereas M2 macrophages express high levels of non-opsonic receptors such as scavenger, mannose and galactose-type receptors [11, 13]. It has been shown that the arginine pathway in M2 macrophages is shifted towards the formation of ornithine which is a key component of collagen, and polyamines involved in cell growth [11, 13, 15]. Nevertheless, the arginine metabolism in M1 macrophages shows predominant levels of inducible nitric oxide synthase (iNOS) followed by the release of effector molecules such as nitric oxide (NO) and related reactive nitrogen intermediates (RNI) [9, 11, 13, 15, 18].
Figure 2â”‚ Overview of M1 and M2 classification . Macrophages can differentiate in response to endogenous or exogenous signals. Exposure to IFN-É£ in the absence or presence of LPS or TNF gives rise to M1 macrophages, while M2 differentiation is driven by a variety of stimuli. M1 macrophage activity is related to Th1 responses, killing of intracellular pathogens and tumor resistance. M2a (induced by exposure to IL-4 and IL-13) and M2b (induced by combined exposure to immune complexes and TLR or IL-1R agonists) are involved in among others Th2 responses, allergy and tumor promotion. The different forms of M2 macrophages share a characteristic phenotype (IL-12low, IL-23low, and IL-10high). However, the production of cytokines differs and depends on the type of stimulus by which the M2 macrophage is generated. On the contrary, M1 macrophages express an IL-10low, IL-12high, Il-23high phenotype.
Macrophages and disease
It has been shown that the pro-inflammatory classically activated macrophages are of importance in host defense during acute infectious diseases among others [1, 17]. Many diseases have been linked to uncontrolled inflammatory cytokine production by macrophages cytokines as well as mediators released by M1 macrophages can lead to tissue damage when M1 activation is not tightly controlled / However, macrophages are not only important in health but also in disease. When M1 macrophage activation is not tightly controlled, an uncontrolled release of pro-inflammatory cytokines as well as mediators by M1 macrophages can lead to tissue damage ; it has been shown that an excessive or a prolonged M1 differentiation in response to acute infection may result in urinary tract infections, gastroenteritis, neonatal meningitis and sepsis among others . Moreover, M1 macrophages are considered as 'key mediators of the immune-pathology that occurs during several autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease' . Besides the beneficial effects for the host such as tissue repair and the encapsulation of parasites, M2 macrophages are also involved in many diseases. An example is their role in tumor promotion and progression [15, 19].
Macrophages in rheumatoid arthritis and osteoarthritis
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and destruction of cartilage and bone often leading to joint disability (van Lent, 1998; van den Berg, 1999; Rampersad, 2009). Macrophages are known to play a key role during inflammation in RA (Kinne, 2000; Szekanecz, 2007); numerous amounts of macrophages are present in the synovial layer as well as the cartilage-pannus junction (Kinne, 2000). Previous research even indicated a positive correlation between the incidence of cartilage destruction and the amount of synovial macrophages being activated (Mulherin, 1996; zie van lent voor referenties!) A significant correlation was found between the number of activated macrophages and occurrence of cartilage destruction (van Lent??). These infiltrated macrophages produce considerable amounts of pro-inflammatory cytokines (e.g. TNFα, IL-1β), chemokines and chemoattractants such as IL-8, and overexpress major histocompatibility complex class II molecules, indicating macrophage activation (reviewed in Kinne et al, 2000). According to Kinne and coworkers, macrophages are related to RA in both acute and chronic phases by their extensive pro-inflammatory, destructive and remodeling capacities and contribution to inflammation as well as cartilage destruction (Kinne, 2002). Moreover, previous research indicated that both synovial inflammation and cartilage destruction were diminished when macrophages were removed from the synovium before or during experimental arthritis (van Lent, 2007; van Lent, 1998 ). However, it is unlikely that macrophages are involved in the initiation process of the pathogenesis in RA (kinne, 2007, zie referentie kinne, 2000). Macrophages are also of importance during osteoarthritis (OA). OA is a syndrome comprising less inflammation compared to RA. Table 1 displays an overview of the similarities and dissimilarities between synovial macrophage present in either RA and OA.
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Table 1. Role of synovial macrophages and their mediators in RA and OA* (Bondeson, 2010)
Synovial macrophages play an important part in driving pathology.
Macrophages drive the production of several proinflammatory cytokines (e.g., IL-6, IL-8).
Macrophages drive the production of several MMPs.
There are fewer macrophages in OA synovium.
IL-1 production is driven by TNF_ in RA but not in OA.
IL-1 is NF-_B dependent in RA but not in OA.
TNF_ is more strongly NF-_B dependent in RA.
There is differential expression of FAK family kinases in RA and OA synovium.
Osteophyte formation is specific for OA.
In experimental OA, osteophyte formation is mediated by macrophages.
* RA = rheumatoid arthritis; OA = osteoarthritis; IL-6 = interleukin-6; MMPs = matrix metalloproteinases; TNFα = tumor necrosis factor α; FAK = focal adhesion kinase.
Damage associated molecular patterns; S100A8 and S100A9.
The recognition of tissue damage in response to damage associated molecular patterns (DAMPs) and reaction to invading microorganisms through pathogen associated molecular patterns (PAMPs) is essential in macrophage activation (van Lent, 2007). Both PAMP and DAMP molecules can be recognized by multiligand receptors for advanced glycation end products (RAGE) and toll-like receptors (TLRs) (zie referentie in Foell, 2007). DAMPS are known to express diverse functionalities within the human body (Foell, 2007; zie referentie in van lent). On the one hand they are involved in cell homeostasis by acting as calcium-binding proteins, chaperones, or chromatin-stabilising molecules (Foell, 2007; zie referentie in van lent). However, during conditions of cell stress these DAMPS are secreted into the extracellular milieu in response to activated or damaged cells and subsequently activate leukocytes and endothelial cells by acting as danger signals (zie Nacken; zie referentie in van lent). DAMPs are also designated as 'alarmins' and 'endokines'. S100 proteins are considered as principal endogenous DAMPs after release by phagocytes responding to inflammatory stimuli (Zoelen, 2009; zie referentie in Foell, 2007). Three Ca2+-binding proteins belonging to the group of S100 proteins -S100A8, S100A9 and S100A12- are predominant within the cytoplasma of meyelomonocytic cells (Sunahorin, 2006; Foell 2004, Phagocyte-specific…). S100A8 and S100A9 proteins are highly released in inflamed tissues as a heterodimeric complex (S100A8/A9) by activated macrophages (reviewed in Sunahori, 2006; Foell, 2007; zie referentie Nacken, 2003(p. 576); van Lent, 2007). This heterodimeric complex is considered as the biologically active form of S100A8 and S100A9 proteins (Roth, 1994; zie Vogl, 2007). In line with the relation of macrophages in autoimmune diseases such as RA, S100A8 and S100A9 are presumed to be concerned in the pathogenesis of RA (zie referentie van lent, 2007). This hypothesis also holds true for the heterodimer S100A8/A9 (zie referentie van Lent, 2007). Several studies reported high amounts of the complex present in the synovial fluid from RA joints (uit Foell, 2004 Phagocyte-specific…: Frosch, 2000; Kane, 2003; Berntzen, 1991; Emery 1988 -> allemaal controleren! Zie ook Sunahori, 2006).The concentrations that were found in the synovial fuid even were up to 10-fold higher compared to S100A8/S100A9 concentration in plasma (zie Foell, 2004). Van Lent and colleagues, 2007, showed that S100A8/A9 can regulate joint inflammation during antigen-induced arthritis (van Lent, 2007). Additionally, it is suggested that S100A8/A9 is involved in the direct regulation of cartilage destruction (Van Lent, 2007).
…. . Recently it is shown that these proteins are also of importance during osteoarthritis (OA). OA is a syndrome comprising less inflammation compared to RA. Stimulation of chondrocytes coming from OA patients with S100A8 and S100A9 seem to provoke an increase in cartilage damage. Moreover, in S100A9 knockout mice a decrease in the level of cartilage damage during OA is observed.
Heteromeric MRP8/MRP14 complexes have been shown to represent their biologically active forms.
Expression of the calcium-binding proteins MRP8 and MRP14 in monocytes is regulated by a calcium-induced suppressor mechanism. J Roth, M Goebeler, V Wrocklage, C van den Bos, and C Sorg
S100 proteins, which mediate inflammatory responses and are involved in the recruitment of inflammatory cells to sites of injury (9, 10), have been suggested to be alarmins. S100 proteins comprise a family with more than 20 members, 3 of which have been linked to innate immune functions by their expression by myeloid cells: S100A8 (also called calgranulin A or myeloid-related protein-8 [MRP8]), S100A9 (MRP14 or calgranulin B), and S100A12 (MRP6 or calgranulin C). Of these, MRP8 and MRP14 form heterodimers, which are the biologically relevant forms of these proteins (11-13). MRP8/14 complexes induce a variety of inflammatory reactions and the extent of MRP8/14 expression correlates with disease activity in several inflammatory disorders (10, 14). We showed that the Toll-like receptor (TLR)-4 complex interacts with MRP8/14 (13). MRP8/14 was found to amplify LPS-induced tumor necrosis factor (TNF)-a release in vitro and in vivo, and mice with a targeted deletion of the mrp14 gene were protected against LPS-induced lethal shock. MRP8 is also almost not detectable at the protein level in mature phagocytes of MRP14- deficient (MRP142/2) mice despite normal MRP8 mRNA levels, probably due to the elevated metabolism of MRP8 in the absence of its binding partner. Thus, targeted deletion of MRP14 leads to a complete lack of a functional MRP8/14 complex in the mouse (13, 15). Moreover, MRP142/2 miceshowed improved survival after intraperitoneal injection of E. coli (13). Van Zoelen.
Rheumatoid arthritis (RA) results in a dysregulated immune response that leads to inflammation and destruction of the synovial linings and joint structures. Crucial to this pathophysiological process are myeloid cells, including neutrophils, monocytes, and macrophages (1, 2), which can produce proinflammatory cytokines and matrix metalloproteinases leading to cartilage degradation and bone destruction (3). The collagen-induced arthritis (CIA) and the K/BxN serum transfer models are two well-established mouse models of inflammatory arthritis that share many features with RA (1, 4). Both models involve inflammatory myeloid cells, develop erosions similar to human RA, and can be used to study the acute (K/ BxN) and chronic (CIA) portions of the human disease (1, 4). The S100 group of proteins is the largest group of calcium-binding proteins within the EF-hand homology family (5). S100A8 (calgranulin A, MRP8) and S100A9 (calgranulin B, MRP14) are highly expressed in activated and circulating myeloid cells and form stable heterodimers that are secreted upon stimulation (5). Increased local and systemic protein expression has been linked to inflammatory diseases, including RA, since the 1980s (2, 5, 6). Previous studies have implicated a role for S100A9/S100A8 in experimental inflammatory arthritis models (2, 7) and in human autoimmune-mediated diseases including RA (2, 6), Sjo¨gren's syndrome, systemic lupus erythematosus, and inflammatory bowel disease [all reviewed in (5)]. Rampersad, 2009
S100A8 has been shown to be the active component of this complex whereas S100A9 exhibits rather regulatory functions and protects S100A8 from degradation.13 However, inflammatory mediators such as interleukin (IL)1, tumour necrosis factor (TNF)a or interferon (IFN)c stimulate macrophages to upregulate and secrete S100A8/S100A9 and it is now clear that S100A8/S100A9 induces proinflammatory responses in leucocytes and endothelial cells.13 14 Van Lent, 2007
S100 proteins: S100A8 and S100A9
Functions, role of S100A8 and S100A9 in M1-M2 macrophage biology.
It is of interest to study the role of S100A8 and S100A9 in M1-M2 macrophage biology. Therefore, it was examined if M1 differentiated macrophages produce more S100A8 and S100A9 than M2 in vitro, and if S100A8 and S100A9 stimulation promotes the differentiation towards M1 or M2 macrophages. Based on literature, it was hypothesized that…. Role of S100 proteins in chondrocytes…
S100A8 and S100A9 proteins are important during rheumatoid arthritis (RA). These pro-inflammatory proteins are able of inducing the immune system and can cause inflammation and cartilage damage. Recently it is shown that these proteins are also of importance during osteoarthritis (OA). OA is a syndrome comprising less inflammation compared to RA. Stimulation of chondrocytes coming from OA patients with S100A8 and S100A9 seem to provoke an increase in cartilage damage. Moreover, in S100A9 knockout mice a decrease in the level of cartilage damage during OA is observed.
Macrophages and monocytes are important producers of both S100A8 and S100A9 and are probably related to the activation of chondrocytes and the breakdown of cartilage during OA. It is hypothesized that macrophages and monocytes of OA patients have increased production levels of S100A8 and S100A9 compared to healthy controls. Classical pro-inflammatory macrophages (M1) possibly produce more S100 protein than anti-inflammatory M2 macrophages.
S100A8 is complex because of intrecellular and extracellular functions… zie Sunahori, 2010.
A whole variety of different intra- and extracellular functions has been described for S100 proteins. The specificity of interactions with several intracellular target proteins seems to depend on the subcellular distribution and dynamically regulated tissue-specific expression. Therefore, the suggested intracellular functions are particularly diverse. Extracellular activities, mainly described in the context of either trophic effects on the central nervous system or regulatory effects on inflammatory cells, are also poorly understood up to date [24,25]. Foel, 2004 Phagocyte-specific…
Three phagocyte-specific S100 proteins comprise the group of calgranulins. The three members of this protein group, S100A8, S100A9 and S100A12 are characterized by a unique expression pattern, with prevalence in cells of myeloid origin. The heterodimer of S100A8 and S100A9 was also known as cystic fibrosis antigen [5,41]. This complex was also called ''leukocyte protein L1'' and is still designated as calprotectin by some research groups [42,43]. Taken together, the calgranulins contribute approximately 50% of the soluble cytosolic content of granulocytes [44,45]. The expression in myeloid cells, release by activated phagocytes, and pro-inflammatory effects soon pointed to a prominent role in host defense and inflammation. The expression of S100A8 and S100A9 seems to be restricted to early stages of myeloid differentiation, since it is present in circulating granulocytes and monocytes, but not in resting tissue macrophages [4,46]. Phagocytes expressing S100A8 and S100A9 belong to the first cells infiltrating inflammatory lesions [3,4]. Furthermore, expression in inflammatory altered keratinocytes, epidermis and in malignant disorders have been observed [47,48]. In general, S100A8 and S100A9 are expressed as a heterodimer, but differential expression of S100A8 and S100A9 has been found to indicate a chronic type of inflammatory reactions in glomerulonephritis and in chronic renal allograft rejection [49,50]. S100A8 and S100A9 are mainly localized in the cytosol of phagocytes but may translocate to the cytoskeleton and to membranes upon elevations of intracellular calcium concentrations . They are involved in cytoskeletal rearrangement and cell migration . In addition, S100A8/S100A9 play a role in the arachidonic acid metabolism of granulocytes and in the regulation of the neutrophilic NADPH-oxidase [53,54]. Foel, 2004 Phagocyte-specific…
Finally, human monocytes differentiated with granulocyte-macrophage colony stimulating factor (GM-CSF) or M-CSF have M1 and M2 properties, respectively, and have been referred to as Mø1 and Mø2 .