Macrophages are heterogeneous and their phenotype and functions are regulated by the surrounding micro-environment. Macrophages commonly exist in two distinct subsets: 1) Classically activated or M1 macrophages, which are pro-inflammatory and polarized by lipopolysaccharide (LPS) either alone or in association with Th1 cytokines such as IFN-γ, GM-CSF, and produce pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, IL-12, IL-23, and TNF-α; and 2) Alternatively activated or M2 macrophages, which are anti-inflammatory and immunoregulatory and polarized by Th2 cytokines such as IL-4 and IL-13 and produce anti-inflammatory cytokines such as IL-10 and TGF-β. M1 and M2 macrophages have different functions and transcriptional profiles. They have unique abilities by destroying pathogens or repair the inflammation-associated injury. It is known that M1/M2 macrophage balance polarization governs the fate of an organ in inflammation or injury. When the infection or inflammation is severe enough to affect an organ, macrophages first exhibit the M1 phenotype to release TNF-α, IL-1β, IL-12, and IL-23 against the stimulus. But, if M1 phase continues, it can cause tissue damage. Therefore, M2 macrophages secrete high amounts of IL-10 and TGF-β to suppress the inflammation, contribute to tissue repair, remodeling, vasculogenesis, and retain homeostasis. In this review, we first discuss the basic biology of macrophages including origin, differentiation and activation, tissue distribution, plasticity and polarization, migration, antigen presentation capacity, cytokine and chemokine production, metabolism, and involvement of microRNAs in macrophage polarization and function. Secondly, we discuss the protective and pathogenic role of the macrophage subsets in normal and pathological pregnancy, anti-microbial defense, anti-tumor immunity, metabolic disease and obesity, asthma and allergy, atherosclerosis, fibrosis, wound healing, and autoimmunity.

Macrophage plasticity, polarization, and function in health and disease.

Inflammation in wound repair: molecular and cellular mechanisms.

Observational studies of necrotic core progression identify intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization. The rapid accumulation of erythrocyte membranes causes an abrupt change in plaque substrate characterized by increased free cholesterol within the lipid core and excessive macrophage infiltration. Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. Intimal neovascularization is predominantly thought to arise from the adventitia, where there are a plethora of pre-existing vasa vasorum. In lesions that have early necrotic cores, the majority of vessels invading from the adventitia occur at specific sites of medial wall disruption. A breech in the medial wall likely facilitates the rapid in-growth of microvessels from the adventitia, and exposure to an atherosclerotic environment stimulates abnormal vascular development characterized by disorganized branching and immature endothelial tubes with "leaky" imperfect linings. This network of immature blood vessels is a viable source of intraplaque hemorrhage providing erythrocyte-derived phospholipids and free cholesterol. The rapid change in plaque substrate caused by the excessive accumulation of erythrocytes may promote the transition from a stable to an unstable lesion. This review discusses the potential role of intraplaque vasa vasorum in lesion instability as it relates to plaque rupture.

Atherosclerotic Plaque Progression and Vulnerability to Rupture Angiogenesis as a Source of Intraplaque Hemorrhage

Inflammatory cells during wound repair: the good, the bad and the ugly

The macrophage is a prominent inflammatory cell in wounds, but its role in healing remains incompletely understood. Macrophages have many functions in wounds, including host defence, the promotion and resolution of inflammation, the removal of apoptotic cells, and the support of cell proliferation and tissue restoration following injury. Recent studies suggest that macrophages exist in several different phenotypic states within the healing wound and that the influence of these cells on each stage of repair varies with the specific phenotype. Although the macrophage is beneficial to the repair of normally healing wounds, this pleotropic cell type may promote excessive inflammation or fibrosis under certain circumstances. Emerging evidence suggests that macrophage dysfunction is a component of the pathogenesis of nonhealing and poorly healing wounds. As a result of advances in the understanding of this multifunctional cell, the macrophage continues to be an attractive therapeutic target, both to reduce fibrosis and scarring, and to improve healing of chronic wounds.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/9B0BF84E8A239160D32F2EE8214633D3/S1462399411001943a.pdf/div-class-title-inflammation-and-wound-healing-the-role-of-the-macrophage-div.pdf

Inflammation and wound healing: the role of the macrophage.

Adenosine A2A receptor (A2AR) agonists synergize with Escherichia coli (E. coli) LPS [toll-like receptor (TLR)4 agonist] to up-regulate vascular endothelial growth factor (VEGF) expression in murine macrophages. Here, we demonstrate that TLR2, TLR7, and TLR9, but not TLR3 and TLR5 agonists, also synergize with A2AR agonists and adenosine to up-regulate VEGF, while simultaneously strongly down-regulating TNFα expression. In the absence of adenosine or A2AR agonists, Porphyromonas gingivalis (P. gingivalis) LPS and PAM3CAG (TLR2 agonists), resiquimod (R848) (TLR7 agonist), and non-methylated CpG DNA (TLR9 agonist) strongly up-regulate TNFα expression, with no effect on VEGF. In the presence of adenosine or A2AR agonists, but not A1R agonists, TLR2, 4, 7, and 9 agonists strongly up-regulate VEGF expression, while simultaneously down-regulating TNFα. C57BL/10ScN (TLR4 deletion mutant) macrophages produce TNFα in response to TLR2, 3, 7, and 9 agonists, but not the TLR4 agonist E. coli LPS. With adenosine or A2AR agonists, TLR2, 7, and 9, but not TLR4 agonists, also synergistically up-regulate VEGF, while down-regulating TNFα expression. Polyinosinic-polycytidilic acid (poly(I:C)) (TLR3 agonist) stimulates TNFα expression in macrophages from both C57BL/10ScSn and C57BL/10ScN mice, but has little effect on VEGF expression in the presence of adenosine or A2AR agonists. R-flagellins from Serratia marcescens (S. marcescens) and Salmonella muenchen (S. muenchen) do not stimulate TNFα expression in either C57BL/10ScSn or C57BL10/ScN mice, and have no effect on VEGF production in the presence of adenosine or A2AR agonists. While adenosine and A2AR agonists strongly down-regulate TNFα protein expression induced by TLR2, 3, 4, 7, and 9 agonists, TNFα mRNA and NF-κB activation are not reduced. We propose a novel signaling pathway in murine macrophages involving synergy between TLRs 2, 4, 7, and 9 and A2ARs, that up-regulates VEGF and down-regulates TNFα expression, thus acting as an angiogenic switch. This angiogenic switch may play an important role in ischemia when TLR agonists are present, providing an interface between innate immunity and wound healing.

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An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

Murine macrophages are activated by interferon-γ (IFN-γ) and/or Toll-like receptor (TLR) agonists such as bacterial endotoxin (lipopolysaccharide [LPS]) to express an inflammatory (M1) phenotype characterized by the expression of nitric oxide synthase-2 (iNOS) and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-12. In contrast, Th2 cytokines IL-4 and IL-13 activate macrophages by inducing the expression of arginase-1 and the anti-inflammatory cytokine IL-10 in an IL-4 receptor-α (IL-4Rα)-dependent manner. Macrophages activated in this way are designated as "alternatively activated" (M2a) macrophages. We have shown previously that adenosine A2A receptor (A(2A)R) agonists act synergistically with TLR2, TLR4, TLR7, and TLR9 agonists to switch macrophages into an "M2-like" phenotype that we have termed "M2d." Adenosine signaling suppresses the TLR-dependent expression of TNF-α, IL-12, IFN-γ, and several other inflammatory cytokines by macrophages and induces the expression of vascular endothelial growth factor (VEGF) and IL-10. We show here using mice lacking a functional IL-4Rα gene (IL-4Rα(-/-) mice) that this adenosine-mediated switch does not require IL-4Rα-dependent signaling. M2d macrophages express high levels of VEGF, IL-10, and iNOS, low levels of TNF-α and IL-12, and mildly elevated levels of arginase-1. In contrast, M2d macrophages do not express Ym1, Fizz1 (RELM-α), or CD206 at levels greater than those induced by LPS, and dectin-1 expression is suppressed. The use of these markers in vivo to identify "M2" macrophages thus provides an incomplete picture of macrophage functional status and should be viewed with caution.

The Adenosine-Dependent Angiogenic Switch of Macrophages to an M2-Like Phenotype is Independent of Interleukin-4 Receptor Alpha (IL-4Rα) Signaling

Placenta formation occurs through a complex and coordinated effort between the fetus’s extraembryonic tissues and the gravid endometrial tissues. Many macrophages are present in the placenta throughout pregnancy and have been detected as early as day 10 of pregnancy (Chang et al., 1993). Placental macrophages include Hofbauer cells of the fetal chorionic villi and decidual macrophages of the maternal decidua basalis (Figure 1) (Bulmer & Johnson, 1984). Functions of placental macrophages include the production of substances that regulate local immune reactions (such as factors that regulate maternal immunological tolerance and fetal protection) and that promote angiogenesis in the placenta during its development (Mues et al., 1989; Sevala et al., 2007). Although they represent a significant presence on both the maternal and fetal sides of the placenta, placental macrophage functions have not been completely elucidated and still remain a significantly studied area of investigation.

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The Role of Macrophages in the Placenta

The sternalis is an uncommon, variant muscle of the anterior thoracic wall that is estimated to be present in 8% of the human population. Students in a medical gross anatomy course were fortunate to discover a right, unilateral sternalis muscle during dissection of a female cadaver. Despite its rarity, radiologists must be aware of the possibility of encountering the sternalis during thoracic imaging (CT scans, mammography, MRI) because of the risk for its misdiagnosis as a tumor. Further, risk for surgical complications such as damage to this muscle during breast surgery must be considered. Thus, although it may be difficult to perform a proper anatomic analysis of the infrequently observed sternalis muscle, it is important that students and clinicians be aware of its existence because of its potentially significant impact on clinical diagnosis and patient management.

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Sternalis muscle: importance of its awareness in chest imaging and clinical significance

In medical education, human anatomy is a content rich and conceptually challenging course that can overwhelm the students. We have found team-based learning (TBL), which engages students in their learning, to be an ideal pedagogical strategy to teach anatomy. TBL combines various aspects of the adult learning theories in a unique way where learning is self-directed and at the same time, guided by the faculty. The concept of TBL focuses on learning defined by pre-class preparation of “content specific learning topics” and subsequent in-class team discussion. Team discussion is a form of peer teaching that allows students to reflect upon their learning and remediate any knowledge deficits.

Grace Pinhal-Enfield

Papers

An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

The Adenosine-Dependent Angiogenic Switch of Macrophages to an M2-Like Phenotype is Independent of Interleukin-4 Receptor Alpha (IL-4Rα) Signaling

The Role of Macrophages in the Placenta

Sternalis muscle: importance of its awareness in chest imaging and clinical significance

Team-Based Learning: An Effective Pedagogical Strategy to Teach Anatomy