Macrophage Function Advanced article Disorders Article Contents . Introduction Dawn ME Bowdish, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK . Immune Activation . Macrophage Functions Siamon Gordon, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK . Phagocytosis Based in part on the previous version of this Encyclopedia of Life Sciences . Autophagy (ELS) article, Macrophage Function Disorders by Siamon Gordon. Role in Pathogenesis and Disease . Concluding Remarks Macrophages respond to alterations in their microenvironment by producing a wide . Acknowledgements variety of products that mediate inflammation, immunity and tissue homeostasis or Online posting date: 15th March 2009 injury. Macrophage recognize pathogen-associated molecular patterns (e.g. bacterial products) and endogenous ligands (e.g. apoptotic cells) through a broad and adaptable range of pattern-recognition receptors. The consequence of this recognition is generally effective clearance via phagocytosis; however, when this is not effective macrophages may become inappropriately activated and initiate an inappropriate inflammatory response. Although primary deficiencies of macrophage function in human disease are relatively uncommon, there is increasing evidence that even subtle genetic changes in macrophage function contribute to altered responses to both acute infections and in many major acquired disease processes such as autoimmunity, inflammatory diseases and cancer. Introduction disease by producing secretory products or by altering functional phenotype, which can be characterized by The macrophages of the body represent a widely dispersed changes in expression of their receptors (for further infor- family of cells, many of which are highly phagocytic, and mation, see Taylor et al., 2005). Herein we discuss a subset display considerable heterogeneity, depending on their of macrophage functions, focussing especially on their role tissue microenvironment and stimulation by a range of in infectious and chronic disease, and highlight recent ad- infectious and antigenic agents. They are relatively long- vances in human genetics that contribute to our under- lived, biosynthetically active cells and express diverse sur- standing of macrophage function disorders. face receptors and secretory products. They adapt readily to changes in their milieu and help to maintain homeostasis locally and systemically. If unable to deal adequately with Immune Activation an infectious or injurious stimulus, macrophages initiate a chronic inflammatory process which contributes to per- Macrophages and their close antigen-presenting cell (APC) sistent tissue damage; they can also mediate acute, some- relations, dendritic cells, play an important role in innate times massive, responses from other cell types and organ immunity, as well as in the acquired response. Macro- systems. See also: Inflammation: Chronic; Macrophages phages and dendritic cells capture particulate and soluble Although primary deficiencies of macrophage function antigens at body surfaces and at other sites outside sec- are relatively uncommon, macrophages contribute to, and ondary lymphoid organs through a range of recognition play a central role in, many major disease processes. These receptors, including mannose and scavenger receptors. include storage diseases, chronic infections and immunol- Ligation of these and other receptors by microbial ligands ogical disorders, as well as responses to metabolic injury can induce the rapid migration of APCs to draining lymph (Table 1). Macrophages may participate in the pathology of nodes, for induction or suppression of an immune response. Langerhans cells in skin and other complex ep- ithelia are particularly important in this regard and re- spond to lipopolysaccharide (LPS) and cytokines such as ELS subject area: Immunology tumour necrosis factor a (TNF-a), by migration and differ- entiation into dendritic cells. Although the role of ma- How to cite: crophages per se in immune induction is poorly Bowdish, Dawn ME; and, Gordon, Siamon (March 2009) Macrophage understood, its contribution to oxidative and other effec- Function Disorders. In: Encyclopedia of Life Sciences (ELS). John Wiley & tor mechanisms in cellular and humoral immunity is with- Sons, Ltd: Chichester. out question. Macrophages also contribute to host defence DOI: 10.1002/9780470015902.a0002174.pub2 to viruses and other microorganisms, as well as to ENCYCLOPEDIA OF LIFE SCIENCES # 2009, John Wiley & Sons, Ltd. www.els.net 1 Macrophage Function Disorders Table 1 Diseases in which macrophages play a significant role Type Example Mechanism Storage Gaucher disease Genetic lysosomal hydrolase deficiency Haemosiderosis Secondary Fe2+ accumulation in reticulo-endothelial system Haemochromatosis Primary Fe2+ overload (also other tissues) Chronic inflammation Silicosis Asbestosis Nondegradable, bioactive particle accumulation in lung and pleura Rheumatoid arthritis Autoimmune destruction Inflammatory bowel disease Defects in intracellular sensing of bacteria lead to a skewed cytokine response Infection Septic shock (Gram- Release of vasoactive mediators and cytokines, especially negative, Gram-positive) tumour necrosis factor a and interleukin 1b Tuberculosis Cellular immunity activates Macrophage, via interferon g Malaria Uptake of parasitized erythrocytes and release of mediators AIDS (acquired Human immunodeficiency virus (HIV) infects immunodeficiency Macrophage and CD4 T cells leading to failure of cellular syndrome) immunity Dengue virus Antibody-dependent enhancement leads to increased infection of FcgR expressing cells Metabolic injury Atherosclerosis Oxidized lipoproteins induce foam cell formation in major arteries Alzheimer’s disease Nondegradable amyloid peptide induces Macrophage secretion of neurotoxic products Malignancy Cancer Macrophage within the tumour microenvironment facilitate angiogenesis, extracellular matrix remodelling and promote tumour cell motility autoimmune tissue injury by antibody and complement- by IFNg is central to host resistance to many intracellular dependent cytotoxicity and clearance, involving fragment pathogens as it induces the production of nitric oxide crystalline (Fc) and complement receptors, often working synthase (iNOS) and superoxide radicals as well as a in collaboration. See also: Antigen-presenting Cells; number of proteolytic enzymes (Figure 1a). Failure to pro- Cytokines; Inflammatory Mediators; Natural Killer duce or respond to this cytokine as a result of recessive (NK) Cells; T Lymphocytes: Helpers genetic defects results in persistent or disseminated myco- The phenotype of macrophage activation covers a spec- bacterial and other infections in mice and humans and life- trum from classic immune activation, which is essential for threatening opportunistic infections in acquired immune cellular immunity and antimicrobial resistance, to deactiva- deficiency syndrome (AIDS). The macrophage contributes tion, which is characterized by prominent anti-inflammatory to the initial infection, dissemination and persistence of effects and is essential for the resolution of inflammation. human immunodeficiency virus type 1 (HIV-1), and may be Interleukin 4 (IL-4) and IL-13 induce a distinct, alternate responsible for neuropathology. Known factors that influ- type of activation in which major histocompatibility com- ence infection of macrophages by different HIV strains in- plex (MHC) class II antigen expression and mannose recep- clude CD4 and chemokine coreceptors for viral entry. tor-mediated endocytosis are enhanced, favouring humoral See also: AIDS: Clinical Manifestations immunity. Figure 1 describes the four major forms of acti- IFNg-activated macrophages also contribute to tissue vated macrophages. See also: Cytokines as Mediators of injury in delayed-type hypersensitivity reactions, by en- Disease; Lymphoid System; Tumour Necrosis Factors hanced cytocidal activity and mediator production. Such macrophages are primed to respond to LPS and other mi- Classical activation crobial ligands by massive release of cytokines such as TNFa, contributing to direct endothelial injury and septic Exposure to interferon g (IFNg) and a toll-like receptor shock. The effector mechanisms are regulated by opposing (TLR) agonist (e.g. microbes or their products) results in receptor and signalling pathways of which several have macrophages that are said to be classically activated. These been recently studied intensively. These include pro- macrophages express high levels of MHC and CD80/86, inflammatory cascades (CD14, TLRs, nuclear factor-kB which increases their capacity as APCs. Immune activation (NF-kB)) and possible anti-inflammatory, downregulatory 2 ENCYCLOPEDIA OF LIFE SCIENCES # 2009, John Wiley & Sons, Ltd. www.els.net Macrophage Function Disorders Classical activation Alternative activation Bacterial component (TLR stimulus) IL-4/IL-13 Dectin-1 +++ MHC T cell Mannose − receptor +++ NO, O Arginase Chemokines, CCR7 e.g. MDC, TARC MHCII (a) (b) Innate activation Deactivation Bacterial component IL-10, glucocorticoids MARCO CD163 (TLR stimulus) CD200 Blockade of T cell responses STAT3 STAT3 regulated genes Inhibition of pro-inflammatory − cytokine production (c) (d) Figure 1 Macrophage activation phenotypes. mechanisms involving scavenger and other receptors which inflammatory reactions, and the induction of humoral promote LPS clearance. See also: Hypersensitivity: responses. T Lymphocyte-mediated (Type IV) Alternative activation Innate activation