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Background & Aims: Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver leads to long-term alterations to the liver macrophage compartment., Methods: We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single-cell CITE-sequencing, single-nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection., Results: We show that T. brucei brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection., Conclusion: Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term., Impact and Implications: Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c + monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206 + MhcII hi and Timp2 + MhcII lo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206 + Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206 + Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation., (© 2022. The Author(s).)

Efficient priming of anti-tumor T cells requires the uptake and presentation of tumor antigens by immunogenic dendritic cells (DCs) and occurs mainly in lymph nodes draining the tumor (tdLNs). However, tumors expand and activate myeloid-derived suppressor cells (MDSCs) that inhibit CTL functions by several mechanisms. While the immune-suppressive nature of the tumor microenvironment is largely documented, it is not known whether similar immune-suppressive mechanisms operate in the tdLNs. In this study, we analyzed MDSC characteristics within tdLNs. We show that, in a metastasis-free context, MO-MDSCs are the dominant MDSC population within tdLNs, that they are highly suppressive and that tumor proximity enhances their recruitment to tdLN via a CCR2/CCL2-dependent pathway. Altogether our results uncover a mechanism by which tumors evade the immune system that involves MDSC-mediated recruitment to the tdLN and the inhibition of T-cell activation even before reaching the highly immunosuppressive tumor microenvironment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The liver is a major target organ for metastasis of both gastrointestinal and extra-gastrointestinal cancers. Due to its frequently inoperable nature, liver metastasis represents a leading cause of cancer-associated death worldwide. In the past years, the pivotal role of the immune system in this process is being increasingly recognised. In particular, the role of the hepatic macrophages, both recruited monocyte-derived macrophages (Mo-Mfs) and tissue-resident Kupffer cells (KCs), has been shown to be more versatile than initially imagined. However, the lack of tools to easily distinguish between these two macrophage populations has hampered the assignment of particular functionalities to specific hepatic macrophage subsets. In this Review, we highlight the most remarkable findings regarding the origin and functions of hepatic macrophage populations, and we provide a detailed description of their distinct roles in the different phases of the liver metastatic process., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Macrophage migration inhibitory factor (MIF) was first described as a cytokine 50 years ago, and emerged in mammals as a pleiotropic protein with pro-inflammatory, chemotactic, and growth-promoting activities. In addition, MIF has gained substantial attention as a pivotal upstream mediator of innate and adaptive immune responses and with pathologic roles in several diseases. Of less importance in mammals is an intrinsic but non-physiologic enzymatic activity that points to MIF's evolution from an ancient defense molecule. Therefore, it is not surprising that mif-like genes also have been found across a range of different organisms including bacteria, plants, protozoa, helminths, molluscs, arthropods, fish, amphibians and birds. While Genebank analysis identifying mif-like genes across species is extensive, contained herein is an overview of the non-mammalian MIF-like proteins that have been most well studied experimentally. For many of these organisms, MIF contributes to an innate defense system or plays a role in development. For parasitic organisms however, MIF appears to function as a virulence factor aiding in the establishment or persistence of infection by modulating the host immune response. Consequently, a combined targeting of both parasitic and host MIF could lead to more effective treatment strategies for parasitic diseases of socioeconomic importance., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Macrophage migration inhibitory factor (MIF) was first described as a cytokine 50 years ago, and emerged in mammals as a pleiotropic protein with pro-inflammatory, chemotactic, and growth-promoting activities. In addition, MIF has gained substantial attention as a pivotal upstream mediator of innate and adaptive immune responses and with pathologic roles in several diseases. Of less importance in mammals is an intrinsic but non-physiologic enzymatic activity that points to MIF's evolution from an ancient defense molecule. Therefore, it is not surprising that mif-like genes also have been found across a range of different organisms including bacteria, plants, ‎protozoa, helminths, molluscs, arthropods, fish, amphibians and birds. While Genebank analysis identifying mif-like genes across species is extensive, contained herein is an overview of the non-mammalian MIF-like proteins that have been most well studied experimentally. For many of these organisms, MIF contributes to an innate defense system or plays a role in development. For parasitic organisms however, MIF appears to function as a virulence factor aiding in the establishment or persistence of infection by modulating the host immune response. Consequently, a combined targeting of both parasitic and host MIF could lead to more effective treatment strategies for parasitic diseases of socioeconomic importance., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Myeloid-derived suppressor cells are immature myeloid cells, consisting of a monocytic and a granulocytic fraction, that are known to suppress anti-tumor immune responses. Important targets of the immunosuppressive capacity of MDSC are CD8(+) T cells, which are crucial cytotoxic effector cells in immunotherapeutic settings. CD8(+) T-cell activation and differentiation comprises a well-orchestrated series of events, starting from early TCR-mediated signaling and leading to cytokine secretion, the expression of activation markers, proliferation and the differentiation into several subsets of effector and memory cells. In this review, we summarize the available data on how the production of reactive oxygen species, nitric oxide, the arginase-mediated depletion of l-arginine and Cystine depletion by MDSCs interfere with the signaling molecules necessary for normal CTL differentiation and activation., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

In vivo imaging technology holds promise for refined monitoring of inflammation, both in the clinic and in preclinical animal models, with applications including improved diagnosis, prognosis and therapy monitoring. In particular, molecular imaging, aimed at non-invasively studying molecular and cellular processes in intact organisms, can hereby not only provide information about the amount of inflammation, but also on the type of inflammation and on cells and/or receptors involved. Hereto, an important requisite is the availability of the proper biomarkers and specific probes for targeting these biomarkers. In the current review, we focus on a number of markers on inflamed endothelium and infiltrating myeloid cells (including macrophages) as interesting targets for tracking inflammatory reactions and argue that such markers are not only useful in case of inflammatory diseases of infectious or autoimmune origin, but also for monitoring cancer evolution through the associated inflammation. We elaborate on nanobodies as innovative, specific probes to target these inflammation-associated markers for in vivo molecular imaging., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

In this issue of Blood, Willenborg and colleagues uncover the timeline of monocyte/macrophage involvement during sequential phases of skin wound healing. The CCR2-mediated recruitment of a vascular endothelial growth factor A(VEGF-A)–expressing inflammatory monocyte subset is critical for early vascular sprouting, while epidermal-derived VEGF-A mediates vascularization in the late wound healing phases (see figure).

E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/β-catenin, PI3K/Akt, Rho GTPase, and NF-κB signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. E-cadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of β-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also E-cadherin-dependent. In addition, the E-cadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of E-cadherin expression in these central orchestrators of the immune system.

Mononuclear phagocytes are amongst the most versatile cells of the body, contributing to tissue genesis and homeostasis and safeguarding the balance between pro- and anti-inflammatory reactions. Accordingly, these cells are notoriously heterogeneous, functioning in distinct differentiation forms (monocytes, MDSC, macrophages, DC) and adopting different activation states in response to a changing microenvironment. Accumulating evidence exists that mononuclear phagocytes contribute to all phases of the cancer process. These cells orchestrate the inflammatory events during de novo carcinogenesis, participate in tumor immunosurveillance, and contribute to the progression of established tumors. At the tumor site, cells such as tumor-associated macrophages (TAM) are confronted with different tumor microenvironments, leading to TAM subsets with specialized functions. A better refinement of the molecular and functional heterogeneity of tumor-associated mononuclear phagocytes might pave the way for novel cancer therapies that directly target these tumor-supporting cells., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Studies in mice have advanced our understanding of the contribution of monocytes to inflammation and immunity. However, the lack of a straightforward and reliable method for the isolation of mouse blood monocytes remains a hurdle. Here we describe a fast and easy method for isolating monocytes from mouse blood based on immuno-magnetic labeling. By negative selection we were able to isolate enriched fractions (>50% purity) of unlabeled monocytes. A subsequent positive selection step resulted in purities of > or =90% viable and functional monocytes. This method is of general use for studying mouse monocyte biology., (2010 Elsevier B.V. All rights reserved.)

Alternatively activated macrophages (AAMs), triggered by interleukin-4 (IL-4) and IL-13, play a modulating role during Th2 cytokine-driven pathologies, but their molecular armament remains poorly characterized. Here, we established E-cadherin (Cdh1) as a selective marker for IL-4/IL-13-exposed mouse and human macrophages, which is STAT6-dependently induced during polarized Th2 responses associated with Taenia crassiceps helminth infections or allergic airway inflammation. The IL-4-dependent, arginase-1/ornithine decarboxylase-mediated production of polyamines is important for maximal Cdh1 induction, unveiling a novel mechanism for IL-4-dependent gene transcription. At the macrophage surface, E-cadherin forms a functional complex with the catenins that accumulates at sites of cell contact. Macrophage-specific deletion of the Cdh1 gene illustrates the implication of E-cadherin in IL-4-driven macrophage fusion and heterotypic interactions with CD103(+) and KLRG1(+) T cells. This study identifies the E-cadherin/catenin complex as a discriminative, partly polyamine-regulated feature of IL-4/IL-13-exposed alternatively activated macrophages that contributes to homotypic and heterotypic cellular interactions.

The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.

Tumors may escape from immune control by the induction of CD11b(+)Gr-1(+) myeloid suppressor cells in the spleen. In this study, we demonstrate that this cell population can be subdivided into a CD11b(hi)Gr-1(int)SSC(lo)Ly6G(neg)M-CSFR(int) immature monocytic fraction and a CD11b(hi+)Gr-1(hi)SSC(hi)Ly6G(hi)M-CSFR(neg) granulocytic fraction. Upon in vitro culture, the monocytic CD11b(+)Gr-1(+) cell fraction is sufficient for cytotoxic T lymphocyte (CTL) suppression, which is linked to the gradual differentiation of these monocytic cells into mature F4/80(+) CD68(+) macrophages. These CTL-suppressive macrophages are alternatively activated (M2), as demonstrated by the expression of known and novel M2 signature genes. In search of M2-associated genes involved in the suppressive activity, it is shown that stimulation of peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibition of phospholipase A(2) (PLA(2)) activity cooperate to alleviate CTL suppression. Of importance, purified tumor-associated macrophages display a similar M2 phenotype and are suppressive for antitumor CTLs, via a mechanism that can be almost completely reversed by PPARgamma ligands. Overall, our data identify PLA(2) and especially PPARgamma as new potential therapeutic targets to subvert macrophage-mediated CTL suppression in cancer.

Compared with type I cytokine-associated myeloid (M1) cells, the molecular repertoire and mechanisms underlying functional properties of type II cytokine-associated myeloid (M2) cells are poorly characterized. Moreover, most studies have been limited to in vitro-elicited M2 cells. Here, comparative gene expression profiling of M1 and M2 cells, elicited in murine models of parasitic infections and cancer, yielded a common signature for in vivo-induced M2 populations independent of disease model, mouse strain, and organ source of cells. Some of these genes, such as cadherin-1, selenoprotein P, platelet-activating factor acetylhydrolase, and prosaposin, had not been documented as associated with M2. Overall, the common signature genes provide a molecular basis for a number of documented or suggested properties of M2, including immunomodulation, down-regulation of inflammation, protection against oxidative damage, high capacity for phagocytosis, and tissue repair. Interestingly, several common M2 signature genes encode membrane-associated markers that could be useful for the identification and isolation of M2. Some of these genes were not induced by IL-4/IL-13 or IL-10 under various in vitro settings and thus were missed in approaches based on in vitro-activated cells, validating our choice of in vivo models for expression profiling of myeloid cells.

Mononuclear phagocytes often function as control switches of the immune system, securing the balance between pro- and anti-inflammatory reactions. For this purpose and depending on the activating stimuli, these cells can develop into different subsets: classically (M1) or alternatively (M2) activated mononuclear phagocytes, the molecular and functional characterization of which is a current topic of investigation. Accumulating evidence suggests that cells of the monocyte/macrophage lineage can be hijacked by tumors for their own benefit. Either as immature cells in the periphery, or as mature macrophages at the tumor site, mononuclear phagocytes are able to influence the behavior of cancer cells, shape the tumor microenvironment and subvert anti-tumor immunity, thereby contributing to tumor growth and progression. This review focuses on the mechanisms behind monocyte/macrophage-mediated tumor promotion and interprets the available data within the M1/M2 conceptual frame.

Natural killer (NK) cells fulfill essential accessory functions for the priming of antigen-specific cytotoxic T lymphocytes (CTLs). On the basis of a NKG2D-ligand-positive tumor model, we obtained results implicating NK-mediated regulatory as well as NK-mediated cytolytic activities in the initiation and persistence of CTL activity. Indeed, CD8(+) T-cell-dependent tumor rejection requires NK cell function in vivo, because tumors will progress both on depletion of NK cells or in the absence of optimal NK activity. Here we provide evidence that the absence of NK cells during subcutaneous tumor growth will abrogate generation of antitumor CTL responses and that this process can be linked to the expansion of alternatively activated monocytes. Indeed, our in vitro studies demonstrate that in splenic cultures from NK-deficient tumor-bearing mice, lack of type 1-associated cytokines correlates with the presence of type 2 (alternatively activated) monocytes and the production of type 2 cytokines. Furthermore, these type 2 monocyte-containing splenic adherent populations potently suppress subsequent memory CTL restimulation. We evaluated the role of NK lytic effector functions in the efficient switch of the immune system toward classical (type 1) activation by including differentially activated monocytic populations as targets in cytotoxicity assays. The results indicate that the accessory function of NK cells depends partially on the ability of activated NK cells to preferentially engage type 2 antigen-presenting cells. Thus, when the immune system tends to be type 2 oriented, NK cells can drive an efficient type 2 --> type 1 switch in the population of antigen-presenting cells to provide signaling for the generation of CTLs.