Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

/pdf/exploring-the-full-spectrum-of-macrophage-activation-b5rnrcgcen.pdf

Exploring the full spectrum of macrophage activation.

Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

/pdf/macrophage-plasticity-and-polarization-in-vivo-veritas-3j0n8qsu6m.pdf

Macrophage plasticity and polarization: in vivo veritas

Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing Finally, we briefly discuss the characterization of macrophage heterogeneity in humans

/pdf/protective-and-pathogenic-functions-of-macrophage-subsets-5d5nlezyqd.pdf

Protective and pathogenic functions of macrophage subsets

https://www.cell.com/immunity/pdf/S1074-7613(10)00173-1.pdf

Alternative Activation of Macrophages: Mechanism and Functions

Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

/pdf/macrophage-biology-in-development-homeostasis-and-disease-2nq2u94n8n.pdf

Macrophage biology in development, homeostasis and disease

Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute AAMs through an IL-4- or IL-13-dependent process. Mice fed a high-fat diet develop increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.

https://science.sciencemag.org/content/sci/332/6026/243.full.pdf

Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis

Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13–expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.

https://www.pnas.org/content/pnas/107/25/11489.full.pdf

Systemically dispersed innate IL-13-expressing cells in type 2 immunity.

Parasitic helminths and allergens induce a type 2 immune response leading to profound changes in tissue physiology, including hyperplasia of mucus-secreting goblet cells and smooth muscle hypercontractility. This response, known as 'weep and sweep', requires interleukin (IL)-13 production by tissue-resident group 2 innate lymphoid cells (ILC2s) and recruited type 2 helper T cells (TH2 cells). Experiments in mice and humans have demonstrated requirements for the epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP) and IL-25 in the activation of ILC2s, but the sources and regulation of these signals remain poorly defined. In the small intestine, the epithelium consists of at least five distinct cellular lineages, including the tuft cell, whose function is unclear. Here we show that tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria in mice. After helminth infection, tuft-cell-derived IL-25 further activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells, leading to increased frequencies of both. Tuft cells, ILC2s and epithelial progenitors therefore comprise a response circuit that mediates epithelial remodelling associated with type 2 immunity in the small intestine, and perhaps at other mucosal barriers populated by these cells.

/pdf/tuft-cell-derived-il-25-regulates-an-intestinal-ilc2-27sa0l84ak.pdf

Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit

Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival, and tissue recruitment, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.

/pdf/type-2-innate-lymphoid-cells-control-eosinophil-homeostasis-4rfh9jq7af.pdf

Type 2 innate lymphoid cells control eosinophil homeostasis

Eosinophils in visceral adipose tissue (VAT) have been implicated in metabolic homeostasis and the maintenance of alternatively activated macrophages (AAMs). The absence of eosinophils can lead to adiposity and systemic insulin resistance in experimental animals, but what maintains eosinophils in adipose tissue is unknown. We show that interleukin-5 (IL-5) deficiency profoundly impairs VAT eosinophil accumulation and results in increased adiposity and insulin resistance when animals are placed on a high-fat diet. Innate lymphoid type 2 cells (ILC2s) are resident in VAT and are the major source of IL-5 and IL-13, which promote the accumulation of eosinophils and AAM. Deletion of ILC2s causes significant reductions in VAT eosinophils and AAMs, and also impairs the expansion of VAT eosinophils after infection with Nippostrongylus brasiliensis, an intestinal parasite associated with increased adipose ILC2 cytokine production and enhanced insulin sensitivity. Further, IL-33, a cytokine previously shown to promote cytokine production by ILC2s, leads to rapid ILC2-dependent increases in VAT eosinophils and AAMs. Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation.

/pdf/innate-lymphoid-type-2-cells-sustain-visceral-adipose-tissue-3qq6awrhd0.pdf

Hong-Erh Liang

Papers

Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis

Systemically dispersed innate IL-13-expressing cells in type 2 immunity.

Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit

Type 2 innate lymphoid cells control eosinophil homeostasis

Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages