Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno-metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes.

Haim Shapiro

Aviv Lutaty

Amiram Ariel

Macrophages, Meta-Inflammation, and Immuno-Metabolism

The 13&#x2009;kDa heparin-binding growth factor midkine (MK) was originally identified as a molecule involved in the orchestration of embryonic development. Recent studies provided evidence for a new role of MK in acute and chronic inflammatory processes. Accordingly, several inflammatory diseases including nephritis, arthritis, atherosclerosis, colitis, and autoimmune encephalitis have been shown to be alleviated in the absence of MK in animal models. Reduced leukocyte recruitment to the sites of inflammation was found to be one important mechanism attenuating chronic inflammation when MK was absent. Furthermore, MK was found to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells. Here, we review the current understanding of the role of MK in different inflammatory disorders and summarize the knowledge of MK biology.

Ludwig T. Weckbach

Takashi Muramatsu

Barbara Walzog

Midkine in Inflammation

Dietary supplementation with L-arginine was shown to improve immune responses in various inflammatory models. However, the molecular mechanisms underlying L-arginine effects on immune cells remain unrecognized. Herein, we tested the hypothesis that a limitation of L-arginine could lead to the uncoupled state of murine macrophage inducible nitric oxide synthase and, therefore, increase inducible nitric-oxide-synthase-derived superoxide anion formation. Importantly, we demonstrated that L-arginine dose- and time dependently potentiated superoxide anion production in bacterial endotoxin-stimulated macrophages, although it did not influence NADPH oxidase expression and activity. Detailed analysis of macrophage activation showed the time dependence between LPS-induced iNOS expression and increased <svg style="vertical-align:-3.13504pt;width:31.3375px;" id="M1" height="15.35" version="1.1" viewBox="0 0 31.3375 15.35" width="31.3375"  xmlns="http://www.w3.org/2000/svg">
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Michaela Pekarova

Antonin Lojek

Hana Martiskova

Ondrej Vasicek

Lucia Bino

A. Klinke

D. Lau

Radek Kuchta

Jaroslav Kadlec

Radimir Vrba

Lukas Kubala

New Role for L-Arginine in Regulation of Inducible Nitric-Oxide-Synthase-Derived Superoxide Anion Production in Raw 264.7 Macrophages

The role of apoptosis-associated speck-Like protein (ASC) in the assembly of the inflammasome complex within macrophages has been elucidated in several studies. In this particular role, ASC functions as an adaptor protein by linking nod-like receptors (NLRs) and procaspase-1, thereby leading to the activation of caspase-1 to cleave inflammatory cytokines IL-1<i>&#x3b2;</i> and IL-18 and inducing pyroptosis. It has been noted that ASC maintains inflammasome-independent roles, including but not limited to controlling the expression of Dock2 and mitogen-activated protein kinases (MAPK/ERK2) and regulating the NF-<i>&#x03BA;</i>B pathway. This paper will emphasize the major roles of ASC during pathogen infection, the mechanisms by which it mediates inflammation, and discuss its more recently discovered functions.

Hoda Hassan

Amal O. Amer

Cell Intrinsic Roles of Apoptosis-Associated Speck-Like Protein in Regulating Innate and Adaptive Immune Responses

A recombinant <i>Escherichia coli</i> K-12 strain, transformed with a modified bacterial luciferase gene (luxABCDE) from <i>Photorhabdus luminescens</i>, was constructed in order to monitor the activity of various antimicrobial agents on a real-time basis. This <i>E. coli</i>-lux emitted, without any addition of substrate, constitutive bioluminescence (BL), which correlated to the number of viable bacterial cells. The decrease in BL signal correlated to the number of killed bacterial cells. Antimicrobial activity of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and myeloperoxidase (MPO) was assessed. In high concentrations, H<sub>2</sub>O<sub>2</sub> alone had a bacteriocidic function and MPO enhanced this killing by forming hypochlorous acid (HOCl). Taurine, the known HOCl scavenger, blocked the killing by MPO. When <i>E. coli</i>-lux was incubated with neutrophils, similar killing kinetics was recorded as in H<sub>2</sub>O<sub>2</sub>/MPO experiments. The opsonization of bacteria enhanced the killing, and the maximum rate of the MPO release from lysosomes coincided with the onset of the killing.

J. T. Atosuo

E.-M. Lilius

The Real-Time-Based Assessment of the Microbial Killing by the Antimicrobial Compounds of Neutrophils

Macrophages are terminally differentiated cells of the mononuclear phagocyte system that also encompasses dendritic cells, circulating blood monocytes, and committed myeloid progenitor cells in the bone marrow. Both macrophages and their monocytic precursors can change their functional state in response to microenvironmental cues exhibiting a marked heterogeneity. However, there are still uncertainties regarding distinct expression patterns of surface markers that clearly define macrophage subsets, particularly in the case of human macrophages. In addition to their tissue distribution, macrophages can be functionally polarized into M1 (proinflammatory) and M2 (alternatively activated) as well as regulatory cells in response to both exogenous infections and solid tumors as well as by systems biology approaches.

Luca Cassetta

Edana Cassol

Guido Poli

Macrophage Polarization in Health and Disease

Phagocytes are specialized cells of the immune system, designed to engulf and destroy harmful microorganisms inside the newly formed phagosome. The latter is an intracellular organelle that is transformed into a toxic environment within minutes and disappears once the pathogen is destroyed. Reactive oxygen species and reactive nitrogen species are produced inside the phagosome. Intracellular granules or lysosomes of the phagocyte fuse with the phagosome and liberate their destructive enzymes. This process of phagocytosis efficiently protects against most infections; however, some microorganisms avoid their destruction and cause severe damage. To understand such failure of phagosomal killing, we need to learn more about the actual destruction process in the phagosome. This paper summarizes methods to investigate the biochemistry of the phagosome and discusses some of their limitations. In accordance with the nature of the phagosome, the issue of localization and temporal dynamics is emphasized, and recent developments are highlighted.

Oliver N&#252;sse

Biochemistry of the Phagosome: The Challenge to Study a Transient Organelle

Recently, we have reported that, in addition to macrophages, also neutrophil granulocytes can phagocytose apoptotic neutrophils. Based on this finding, we hypothesized that “cannibalistic” neutrophils at sites of acute infection/inflammation play a major role in the clearance of apoptotic neutrophils. Since at sites of infection/inflammation neutrophils are exposed to microbial constituents and proinflammatory cytokines, in the present study we analyzed the effect of TLR-ligands and cytokines on the ability of neutrophils to phagocytose apoptotic cells <i>in vitro</i>. We observed that exposure to ligands of TLR2 (Malp2, Pam3CSK4), TLR4 (LPS), TLR7/TLR8 (R848), and TLR9 (ODN 2006) led to increased phagocytosis of apoptotic cells by neutrophils. In addition, proinflammatory cytokines such as TNF and GM-CSF strongly enhanced the uptake of apoptotic cells by neutrophils. These results support the hypothesis that neutrophils acquire the ability to phagocytose apoptotic cells at sites of acute infection/inflammation and thereby can contribute to the resolution of inflammation.

Lars Hellberg

Sabrina Fuchs

Christoph Gericke

Arup Sarkar

Martina Behnen

Werner Solbach

Tamás Laskay

Proinflammatory Stimuli Enhance Phagocytosis of Apoptotic Cells by Neutrophil Granulocytes

The CD40 ligand (CD40L) and CD40 are two molecules belonging to the TNF/TNF receptor superfamily, and their role in adaptive immune system has widely been explored. However, the wide range of expression of these molecules on hematopoietic as well as nonhematopoietic cells has revealed multiple functions of the CD40/CD40L interactions on different cell types and processes such as granulopoiesis. CD40 triggering on stromal cells has been documented to enhance the expression of granulopoiesis growth factors such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte/monocyte-colony-stimulating factor (GM-CSF), and upon disruption of the CD40/CD40L-signaling pathway, as in the case of X-linked hyperimmunoglobulin M (IgM) syndrome (XHIGM), it can lead to neutropenia. In chronic idiopathic neutropenia (CIN) of adults, however, under the influence of an inflammatory microenvironment, CD40L plays a role in granulocytic progenitor cell depletion, providing thus a pathogenetic cause of CIN.

Irene Mavroudi

Helen A. Papadaki

The Role of CD40/CD40 Ligand Interactions in Bone Marrow Granulopoiesis

Neutrophil granulocytes have the shortest lifespan among leukocytes in the circulation and die via apoptosis. At sites of infection or tissue injury, prolongation of neutrophil lifespan is critical for effective host defense. Apoptosis of inflammatory neutrophils and their clearance are critical control points for termination of the inflammatory response. Evasion of neutrophil apoptosis aggravates local injury and leads to persistent tissue damage. The short-lived prosurvival Bcl-2 family protein, Mcl-1 (myeloid cell leukemia-1), is instrumental in controlling apoptosis and consequently neutrophil lifespan in response to rapidly changing environmental cues during inflammation. This paper will focus on multiple levels of control of Mcl-1 expression and function and will discuss targeting Mcl-1 as a potential therapeutic strategy to enhance the resolution of inflammation through accelerating neutrophil apoptosis.

Eric Milot

János G. Filep

Regulation of Neutrophil Survival/Apoptosis by Mcl-1

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