An important component of the innate immune system is the macrophage. Macrophages are important phagocytes in the host as they serve two general functions. The first is the maintenance of homeostasis, which involves the regulation of iron metabolism, the clearing of apoptotic cells, and tissue regeneration. The second general function is host defense. As an innate immune effector cell, macrophages are involved in the phagocytosis of foreign particles, and the elimination of pathogens. During inflammation, macrophages are primarily derived from precursor monocytes that are derived from the hematopoetic stem cells in the bone marrow and continuously circulate in the bloodstream. These cells constantly replenish tissue macrophages after exiting the bloodstream to reside in the tissue and becoming resident cells. Based on the anatomical site, the macrophages in different tissues are termed osteoclasts (bone), microglia (CNS), Kupffer cells (liver), histiocytes (connective tissue), and alveolar macrophage (lung). These tissue specific macrophages have their own specialized functions in maintaining homeostasis and providing the first line to defense against pathogens.
Macrophages express PRRs that help in identifying DAMPs and PAMPs. They are generally of two types: cell surface receptors such as toll-like receptors (TLRs), mannose receptor and other lectin receptors; and cytosolic receptors, including NOD-like Receptors (NLRs) and RNA helicases. The presence of multiple PRRs helps macrophages to identify a broad range of pathogens. The ligation of these receptors enables macrophage activation. These receptors activate transcription factors such as NF-κB and IRFs that are involved in the synthesis of many proinflammatory cytokines such as IL-1β, TNF, IL-12, IL-6, and IFNγ etc. that play an important role in anti-microbial defense.
Activated macrophages can de novo synthesize and release a large variety of cytokines (i.e., IL-1, IL-lra, IL-6 , IL-8 , IL-10, IL-12, TNF-alpha, interferon (IFN) α, IFN-γ, MCP-1, MCP-3, macrophage migration inhibitory factor (MIF), macrophage colony stimulating factor (M-CSF), granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), MIP-1, MIP-2, leukemia inhibitory factor (LIF), oncostatin M (OSM), transforming growth factor (TGF) -β). Some cytokines can upregulate the production of other cytokines in macrophages for self-amplification of the inflammatory reaction. These cytokines and chemokines are involved in a variety of biological and pathological processes, modulate many macrophage functions, lead to monocyte recruitment, increased lipid oxidation and uptake, compromised cholesterol efflux, SMC proliferation, and ECM remodeling.
Macrophage activation shows remarkable plasticity as their phenotype is regulated by the sum of all environmental signals, with dynamic changes occurring over time. Macrophages can be broadly classified according to their fundamental roles in maintaining different aspects of homeostasis. Classically activated macrophages (CA-Mf) are activated by a combination of IFNγ and TNF. They have been shown to be important to eliminate intracellular pathogens like Leishmania spp. and thus are an important component of the delayed type hypersensitivity reaction. Although they are considered important in host defense against pathogens, their actions need to be regulated as their indiscriminate microbicidal properties can also lead tissue damage to the host that can cause autoimmune diseases.
Regulatory macrophages, (R-Mϕ), a subset of macrophages, in contrast to classically activated macrophages, are characterized by high production of the anti-inflammatory cytokine IL-10 and decreased production of IL-12. R-Mϕ are generated by two signals. The first signal (immune complexes, prostaglandin E2, adenosine, apoptotic cells, etc.) does not significantly induce cytokines on its own, but in combination with a second stimulus like TLR ligands, can subvert macrophage activation to produce anti-inflammatory cytokines. R-Mϕ are thought to be present during the initial innate immune response to control inflammation and also during late stages of the adaptive immune response to limit cytotoxicity. Since they are immuno-suppressive in nature, R-Mϕ can be exploited by different pathogens. Viruses can use antibodies to enhance their ability to infect while inducing the production of anti-inflammatory cytokines. Leishmania spp. and Bacillus anthracis have been shown to induce the production of these Mϕ subsets to establish an infection.
Wound healing macrophages or alternatively activated macrophages (AA-Mϕ) form a third type of macrophages that are derived by IL-4 and/or IL-13 activation. IL-4 is generated by basophils early during an immune response and later by Th2 cells. AA-Mϕ have been shown to be involved in the generation of extracellular matrix by stimulating arginase activity important in clearing helminthes and nematodes. AA-Mϕ have been reported to be more permissive to intracellular pathogens like M. tuberculosis, L. major, and F. tularensis, possibly because they fail to produce nitric oxide. All three populations of activated macrophages govern critical functions in the host, and consequently all of their activation responses must be tightly controlled to avoid potential complications.