Macrophage effector function significantly influences the quality, duration, and magnitude of most inflammatory reactions. Traditionally, macrophages have been described as antigen-presenting phagocytes that secrete pro-inflammatory and antimicrobial mediators.1 Mounting evidence, however, describes a more complex model involving multiple macrophage phenotypes carrying out differential functions and eliciting divergent effects on surrounding cells and tissues. Stein et al. were the first to describe "alternatively" activated macrophages as having a phenotype distinct from what are now called "classically" activated macrophages.2 From this seminal observation, a model of two major macrophage classes has developed. Classically activated macrophages exhibit a Th1-like phenotype, promoting inflammation, extracellular matrix (ECM) destruction, and apoptosis, while alternatively activated macrophages display a Th2-like phenotype, promoting ECM construction, cell proliferation, and angiogenesis. Although both phenotypes are important components of both the innate and adaptive immune systems, the classically activated macrophage tends to elicit chronic inflammation and tissue injury whereas the alternatively activated macrophage tends to resolve inflammation and facilitate wound healing (Figure 1). [Note: for recent reviews on this topic, please see references 3-6]
Figure 1. Schematic of classical (A) versus alternative (B) activation of macrophages depicting the priming signal (classical only) and stimuli, their effects on cellular function, and subsequent effects on surrounding tissue physiology. [Note: figure adapted from Gordon, S. (2003) Nat. Rev. Immunol. 3:23.]
Classically Activated Macrophages
Differentiation of classically activated macrophages requires a priming signal in the form of IFN-gamma7 via the IFN-gamma R.8 When the primed macrophage subsequently encounters an appropriate stimulus, such as bacterial LPS, it becomes classically activated. LPS is first bound by soluble LBP and then by either soluble or membrane-bound CD14. CD14 delivers LPS to the LPS recognition complex,9 which consists of at least TLR410 and MD-2.11 Pathogens and pathogen components are subsequently taken up by phagocytosis12 and delivered to lysosomes where they are exposed to a variety of degradation enzymes including several Cathepsin cysteine proteases.13 Suitable antigens are processed and loaded onto MHC class II molecules in late endocytic compartments and antigen/MHCII complexes as well as co-stimulatory B7 family members are presented to T cells.14
These events are followed closely by a significant change in cellular morph-ology and a dramatic alteration in the secretory profile of the cell. A variety of chemokines including IL-8/CXCL8, IP-10/CXCL10, MIP-1 alpha/CCL3, MIP-1 beta/CCL4, and RANTES/CCL5, are released as chemoattractants for neutrophils, immature dendritic cells, natural killer cells, and activated T cells.15 Further, several pro-inflammatory cytokines are released including IL-1 beta/IL-1F2, IL-6, and TNF-alpha/TNFSF1A.3,4,5,6 TNF-alpha also contributes to the pro-apoptotic activity of the classically activated macrophage.16,17,18 TNF-alpha is accompanied by Fas Ligand/TNFSF6 secretion16 and NO release as a result of iNOS upregulation.19,20,21,22 In addition, the classically activated macrophage releases proteolytic enzymes including MMP-1, -2, -7, -9, and -12, which degrade Collagen, Elastin, Fibronectin, and other ECM components.23,24,25
While the release of these molecules is important for host defense and direction of the adaptive immune system, when uncontrolled they can levy significant collateral damage on the microenvironment. By eliciting massive leukocyte infiltration and flooding the surrounding tissue with inflammatory mediators, pro-apoptotic factors, and matrix degrading proteases, the classically activated macrophage is capable of dismantling tissues to the point of inflicting serious injury. Tissue destruction perpetrated by chronic inflammation has been associated with the development of tumors, type 1 autoimmune diseases, and glomerulonephritis among other pathologies (Figure 1A).4,6
Alternatively Activated Macrophages
Differentiation of alternatively activated macrophages does not require any priming. IL-42 and/or IL-1326 can act as sufficient stimuli. The binding of these factors to their respective receptors is followed by fluid-phase pinocytosis of soluble antigen.27,28,29 Soluble antigen is then loaded onto MHC class II molecules and antigen/MHCII complexes and co-stimulatory B7 family members are subsequently displayed to T cells.14
Similar to the classically activated macrophage, the alternatively activated macrophage changes its cellular morphology and secretory pattern as a result of appropriate stimulation. Leukocytes are attracted by the macrophage via its release of chemokines including MDC/CCL2230,31 PARC/CCL1832,33 and TARC/CCL17.31 Inflammation is counteracted by the release of factors such as IL-1ra/IL-1F3,34 Ym1, Ym2, RELMa,35,36 IL-10,6 and TGF-beta. TGF-beta also functions indirectly to promote ECM building by inducing nearby fibroblasts to produce ECM components.18 The alternatively activated macrophage itself secretes the ECM components, Fibronectin and bIG-H3,37 the ECM cross-linking enzyme, Trans-glutaminase,38 and Osteopontin, which is involved in cell adhesion to the ECM.39
In addition, alternatively activated macrophages upregulate the enzyme Arginase I, which is involved in proline as well as polyamine biosynthesis. Proline promotes ECM construction while polyamines are involved in cell proliferation.19 Other factors secreted by the alternatively activated macrophage that promote cell proliferation include PDGF, IGF, and TGF-beta.18,40 These factors, along with FGF basic, TGF-alpha, and VEGF, also participate in angiogenesis.40,41
The molecules secreted by the alternatively activated macrophage work toward resolution of inflammation and promotion of wound repair due to their anti-inflammatory, fibrotic, proliferative, and angiogenic activities. This macrophage is also especially efficient at combating parasitic infections such as Schistosomiasis. In addition to its beneficial activities, the alternatively activated macrophage has been implicated in several pathologies, the most prominent of which are allergy and asthma (Figure 1B).3,4
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