Tissue niche occupancy determines the contribution of fetal- versus bone-marrow-derived macrophages to IgG effector functions.

Understanding the mechanisms underlying cytotoxic immunoglobulin G (IgG) activity is critical for improving therapeutic antibody activity and inhibiting autoantibody-mediated tissue pathology. While prior research highlights the important role of the mononuclear phagocytic system for removing opsonized target cells, it remains unclear which monocyte or macrophage subsets stemming from fetal or post-natal bone-marrow (BM)-associated definitive hematopoiesis are involved in target cell depletion. By using a titrated irradiation approach as well as Kupffer-cell-specific deletion of activated Fcγ receptor signaling, we establish conditions under which the contribution of BM-derived monocytes versus yolk-sac-derived liver-resident macrophages to cytotoxic IgG activity can be studied.

Transient Kupffer cell depletion and subsequent replacement by infiltrating monocyte-derived cells does not alter the induction or progression of hepatocellular carcinoma.

Due to a combination of rapid disease progression and the lack of curative treatment options, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Infiltrated, monocyte-derived, tumor-associated macrophages are known to play a role in HCC pathogenesis, but the involvement of Kupffer cells (KCs) remains elusive. Here, we used the Clec4F-diphteria toxin receptor transgenic mouse model to specifically investigate the effect of KC depletion on HCC initiation, progression and neoplastic growth following liver resection.

Kupffer Cells Contested as Early Drivers in the Pathogenesis of Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is an idiopathic chronic immune-mediated cholestatic liver disease characterized by fibro-inflammatory bile duct strictures, progressive hepatobiliary fibrosis, and gut-liver axis disruption. The pathophysiology of PSC remains insufficiently characterized, which hampers the development of effective therapies. Hepatic macrophages (MFs) such as Kupffer cells (KCs) are implicated in PSC pathogenesis, but their exact role is unclear.

Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria.

Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections.

IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D.

IL1β is a central mediator of inflammation. Secretion of IL1β typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1β in promoting cancer progression in patients, but the underlying mechanisms are ill-defined.

Hepatocarcinoma Induces a Tumor Necrosis Factor-Dependent Kupffer Cell Death Pathway That Favors Its Proliferation Upon Partial Hepatectomy.

Partial hepatectomy (PH) is the main treatment for early-stage hepatocellular carcinoma (HCC). Yet, a significant number of patients undergo recursion of the disease that could be linked to the fate of innate immune cells during the liver regeneration process. In this study, using a murine model, we investigated the impact of PH on HCC development by bioluminescence imaging and flow cytometry.

Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche.

Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity.

The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages.

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated.

The role of hepatic macrophages in liver metastasis.

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.

Infection in Mice Critically Relies on Mannose Receptor-Mediated Arginase Induction by a KHC1 Kinesin H Chain Homolog.

Arginase activity induction in macrophages is an escape mechanism developed by parasites to cope with the host's immune defense and benefit from increased host-derived growth factor production. We report that arginase expression and activity were induced in macrophages during mouse infection by , a natural parasite of this host. This induction was reproduced in vitro by excreted/secreted factors of the parasite.

Trypanosoma brucei growth control by TNF in mammalian host is independent of the soluble form of the cytokine.

Infection of C57Bl/6 mice by pleomorphic African trypanosomes Trypanosoma brucei and T. congolense is characterized by parasitemia waves coupled with the production of systemic levels of TNF. This cytokine is known to control T.

Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity.

Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity.

MIF-Mediated Hemodilution Promotes Pathogenic Anemia in Experimental African Trypanosomosis.

Animal African trypanosomosis is a major threat to the economic development and human health in sub-Saharan Africa. Trypanosoma congolense infections represent the major constraint in livestock production, with anemia as the major pathogenic lethal feature. The mechanisms underlying anemia development are ill defined, which hampers the development of an effective therapy.

Molecular Imaging with Kupffer Cell-Targeting Nanobodies for Diagnosis and Prognosis in Mouse Models of Liver Pathogenesis.

Purpose: Kupffer cells (KCs), the liver resident macrophages, are important mediators of tissue homeostasis and pathogen clearance. However, depending on the inflammatory stimuli, KCs have been involved in divergent hepato-protective or hepato-destructive immune responses. The versatility of KCs in response to environmental triggers, in combination with the specific biomarkers they express, make these macrophages attractive in vivo targets for non-invasive monitoring of liver inflammation or pathogenicity.

Involvement of connexin43 in acetaminophen-induced liver injury.

Background And Aims: Being goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults.

Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells.

Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engraft in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells.

Iron Homeostasis and Trypanosoma brucei Associated Immunopathogenicity Development: A Battle/Quest for Iron.

African trypanosomosis is a chronic debilitating disease affecting the health and economic well-being of developing countries. The immune response during African trypanosome infection consisting of a strong proinflammatory M1-type activation of the myeloid phagocyte system (MYPS) results in iron deprivation for these extracellular parasites. Yet, the persistence of M1-type MYPS activation causes the development of anemia (anemia of chronic disease, ACD) as a most prominent pathological parameter in the mammalian host, due to enhanced erythrophagocytosis and retention of iron within the MYPS thereby depriving iron for erythropoiesis.

Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+ Monocytes into Macrophages.

Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C- monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C- monocytes remains elusive.

Monitoring liver macrophages using nanobodies targeting Vsig4: concanavalin A induced acute hepatitis as paradigm.

Kupffer cells (KCs) are liver resident macrophages which are important for tissue homeostasis and have been implicated in immunogenic, tolerogenic and pathogenic immune reactions depending on the insult. These cells and the biomarkers they express thus represent interesting in vivo sensors for monitoring liver inflammation. In the current study, we explored whether KCs can be monitored non-invasively using single-photon-emission computed tomography (SPECT) with (99m)Tc labeled nanobodies (Nbs) targeting selected biomarkers.

MIF contributes to Trypanosoma brucei associated immunopathogenicity development.

African trypanosomiasis is a chronic debilitating disease affecting the health and economic well-being of many people in developing countries. The pathogenicity associated with this disease involves a persistent inflammatory response, whereby M1-type myeloid cells, including Ly6C(high) inflammatory monocytes, are centrally implicated. A comparative gene analysis between trypanosusceptible and trypanotolerant animals identified MIF (macrophage migrating inhibitory factor) as an important pathogenic candidate molecule.

African trypanosome control in the insect vector and mammalian host.

The life cycle of African trypanosomes involves adaptations to the defense mechanisms of two completely different hosts, the insect vector Glossina and the mammalian host. This interplay ultimately determines host resistance and/or tolerance to parasite infection. In the tsetse fly, the immune deficiency (IMD)-regulated pathway, the scavenger receptor peptidoglycan-recognition protein LB (PGRP-LB), and the reactive oxygen species (ROS)-mediated response modulate the insect's capacity to transmit the parasite.

A Trypanosoma brucei kinesin heavy chain promotes parasite growth by triggering host arginase activity.

Background: In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells.

Methodology/principal Findings: By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect.

Contribution of myeloid cell subsets to liver fibrosis in parasite infection.

Accumulation of extracellular matrix components secreted by fibroblasts is a normal feature of wound healing during acute inflammation. However, during most chronic/persistent inflammatory diseases, this tissue repair mechanism is incorrectly regulated and results in irreversible fibrosis in various organs. Fibrosis that severely affects tissue architecture and can cause organ failure is a major cause of death in developed countries.

The CD20 homolog Ms4a8a integrates pro- and anti-inflammatory signals in novel M2-like macrophages and is expressed in parasite infection.

Recently, we identified the CD20 homolog Ms4a8a as a novel molecule expressed by tumor-associated macrophages that directly enhances tumor growth. Here, we analyzed Ms4a8a(+) macrophages in M2-associated infectious pathologies. In late-stage Trypanosoma congolense and Taenia crassiceps infections, Ms4a8a expression was detected in hepatic and peritoneal macrophages respectively.