Absence of Tumor Necrosis Factor Supports Alternative Activation of Macrophages in the Liver after Infection with Leishmania major

Published on Jan 19, 2018in Frontiers in Immunology4.716
· DOI :10.3389/fimmu.2018.00001
Shanshan Hu2
Estimated H-index: 2
(UTAS: University of Tasmania),
Cameron Marshall1
Estimated H-index: 1
(UTAS: University of Tasmania)
+ 3 AuthorsHeinrich Körner39
Estimated H-index: 39
(UTAS: University of Tasmania)
The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major in normally resistant C57BL/6J (B6.WT) mice. The underlying pathogenic mechanism of this fatal disease has so far remained elusive. We found that B6.WT mice deficient for the tnf gene (B6.TNF-/-) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon L. major inoculation. Infected B6.TNF-/- mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45+F4/80+CD11bhiLy6Clow) that displayed a M2 macrophage phenotype with high expression of CD206, arginase-1, and IL-6, supporting the notion that IL-6 could be involved in M2 differentiation. In in vitro experiments, we demonstrated that IL-6 upregulated M-CSF receptor expression and skewed monocyte differentiation from dendritic cells to macrophages. This was countered by the addition of TNF. Furthermore, TNF interfered with the activation of IL-6-induced gp130-signal transducer and activator of transcription (STAT) 3 and IL-4-STAT6 signaling, thereby abrogating IL-6-facilitated M2 macrophage polarization. Therefore, our results support the notion of a general role of TNF in the inflammatory activation of macrophages and define a new role of IL-6 signaling in macrophage polarization downstream of TNF.
  • References (58)
  • Citations (23)
📖 Papers frequently viewed together
97 Citations
129 Citations
4 Authors (Damien Platel, ..., Michel Guiguet)
7 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Xinying Li (Hobart Corporation)H-Index: 1
#2A. Bruce Lyons (UTAS: University of Tasmania)H-Index: 18
Last. Heinrich Körner (Hobart Corporation)H-Index: 39
view all 4 authors...
During an immune response inflammatory macrophages with their wide variety of effector mechanisms including the expression of inducible nitric oxide synthase play an important part in the defense against invading pathogens. The inflammatory phenotype requires the presence of TNF which suppresses alternative activation. In the bacterial Listeria monocytogenes infection model inflammatory macrophages are crucial for protection. After infection, TNF-deficient hosts have a similar number of splenic ...
4 CitationsSource
#1Ulrike Schleicher (FAU: University of Erlangen-Nuremberg)H-Index: 23
#2Katrin Paduch (FAU: University of Erlangen-Nuremberg)H-Index: 1
Last. Christian Bogdan (FAU: University of Erlangen-Nuremberg)H-Index: 56
view all 13 authors...
Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice,...
36 CitationsSource
#1Phillip D. Fromm (JCU: James Cook University)H-Index: 13
#2Jessica C. Kling (UQ: University of Queensland)H-Index: 6
Last. Heinrich Körner (Hobart Corporation)H-Index: 39
view all 5 authors...
Induction of inducible nitric oxide synthase (iNOS) in mononuclear phagocytes by IFN-γ and innate tumor necrosis factor (TNF) provide the basis for an effective immune response to the intracellular parasite Leishmania (L.) major. We previously observed a fatal visceral form of leishmaniasis in L. major-infected C57BL/6 TNF-/- mice. To further delineate the protective function of TNF and its receptor requirements, we comparatively assessed L. major-infected C57BL/6 mice that were either deficient...
6 CitationsSource
#1Franz Kratochvill (St. Jude Children's Research Hospital)H-Index: 9
#2Geoffrey Neale (St. Jude Children's Research Hospital)H-Index: 47
Last. Peter J. Murray (St. Jude Children's Research Hospital)H-Index: 65
view all 11 authors...
Summary Cancer can involve non-resolving, persistent inflammation where varying numbers of tumor-associated macrophages (TAMs) infiltrate and adopt different activation states between anti-tumor M1 and pro-tumor M2 phenotypes. Here, we resolve a cascade causing differential macrophage phenotypes in the tumor microenvironment. Reduction in TNF mRNA production or loss of type I TNF receptor signaling resulted in a striking pattern of enhanced M2 mRNA expression. M2 gene expression was driven in pa...
79 CitationsSource
#1Felix HeymannH-Index: 23
#2Julia PeusquensH-Index: 3
Last. Frank TackeH-Index: 66
view all 15 authors...
The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combinin...
104 CitationsSource
#1Camille Bleriot (French Institute of Health and Medical Research)H-Index: 5
#2Théo Dupuis (French Institute of Health and Medical Research)H-Index: 1
Last. Marc LecuitH-Index: 64
view all 6 authors...
Summary Kupffer cells, the phagocytes of fetal origin that line the liver sinusoids, are key contributors of host defense against enteroinvasive bacteria. Here, we found that infection by Listeria monocytogenes induced the early necroptotic death of Kupffer cells, which was followed by monocyte recruitment and an anti-bacterial type 1 inflammatory response. Kupffer cell death also triggered a type 2 response that involved the hepatocyte-derived alarmin interleukin-33 (IL-33) and basophil-derived...
161 CitationsSource
#1Janina Wolf (CAU: University of Kiel)H-Index: 5
#2Stefan Rose-John (CAU: University of Kiel)H-Index: 93
Last. Christoph Garbers (CAU: University of Kiel)H-Index: 25
view all 3 authors...
Abstract Interleukin-6 (IL-6) is a multifunctional cytokine with well-defined pro- and anti-inflammatory properties. Although only small amounts in the picogram range can be detected in healthy humans, IL-6 expression is highly and transiently up-regulated in nearly all pathophysiological states. IL-6 induces intracellular signaling pathways after binding to its membrane-bound receptor (IL-6R), which is only expressed on hepatocytes and certain subpopulations of leukocytes (classic signaling). T...
192 CitationsSource
#1Marcia Nascimento (WashU: Washington University in St. Louis)H-Index: 3
#2Stanley Ching-Cheng Huang (WashU: Washington University in St. Louis)H-Index: 22
Last. Edward J. Pearce (WashU: Washington University in St. Louis)H-Index: 73
view all 9 authors...
Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that both monocyte-derived and resident macrophages are engaged in the response to infection. Infection caused CCR2-dependent increases in numbers of Ly6Chi monocytes in blood and liver a...
43 CitationsSource
#1Ehud Zigmond (TAU: Tel Aviv University)H-Index: 13
#2Shany Samia-Grinberg (TAU: Tel Aviv University)H-Index: 1
Last. Chen Varol (TAU: Tel Aviv University)H-Index: 15
view all 7 authors...
The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF subsets. In this study, we used a murine model of acute liver injury induced by overdose of N- acetyl-p-aminophenol (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP challenge and sta...
158 CitationsSource
#1Peter J. Murray (St. Jude Children's Research Hospital)H-Index: 65
#2Judith E. Allen (Edin.: University of Edinburgh)H-Index: 57
Last. Thomas A. Wynn (NIH: National Institutes of Health)H-Index: 97
view all 25 authors...
Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards enco...
1,828 CitationsSource
Cited By23
#1Diana Bautista (Pontifical Xavierian University)H-Index: 1
#2Camilo Vásquez (Pontifical Xavierian University)H-Index: 3
Last. Juana Angel (Pontifical Xavierian University)H-Index: 20
view all 8 authors...
The origin and function of blood IgM+IgD+CD27+ B cells is controversial, and they are considered a heterogeneous population. Previous staining of circulating B cells of healthy donors with rotavirus fluorescent virus-like particles allowed us to differentiate two subsets of IgM+IgD+CD27+: IgMhi and IgMlo B cells. Here, we confirmed this finding and compared the phenotype, transcriptome, in vitro function, and Ig gene repertoire of these two subsets. Eleven markers phenotypically discriminated bo...
#1Samantha S Beauford (GSU: Georgia State University)
#2Anita Kumari (GSU: Georgia State University)H-Index: 4
Last. Charlie Garnett-Benson (GSU: Georgia State University)H-Index: 6
view all 3 authors...
BACKGROUND: The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. Most immunotherapies rely on induction of CD8+ tumor-specific cytotoxic T cells that are capable of directly killing cancer cells. Tumors, however, utilize a variety of mechanisms that can suppress anti-tumor immunity. CD4+ regulatory T cells can directly inhibit cytotoxic T cell activity and these cells can be recruited, or induced, by cancer cells allowing escape from immune attack. The ...
#1David Pejoski (University of Geneva)
#2Casimir de Rham (Geneva College)
Last. Angela Huttner (Geneva College)
view all 14 authors...
The rVSV-ZEBOV Ebolavirus vaccine confers protection within days after immunization, suggesting the contribution of innate immune responses. We report modulation of rVSV-ZEBOV vaccinee blood CD56+ NK cell numbers, NKG2D or NKp30 surface receptor expression, Killer Immunoglobulin-like Receptor (KIR)+ cell percentages and NK-cell-related genes on day 1 post immunization. Inverse correlations existed between the concentration of several plasma cytokines and inhibitory KIR+ CD56dim or cytokine-respo...
Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5flox/flox (ALK5ΔCD8) mice ...
#1Hellen Weinschutz Mendes (UFPR: Federal University of Paraná)H-Index: 1
#2Angelica Beate Winter Boldt (UFPR: Federal University of Paraná)H-Index: 13
Last. I.J.T. Messias-Reason (UFPR: Federal University of Paraná)H-Index: 10
view all 6 authors...
Background Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease. Methodology We...
#1Pedro L. Valenzuela (University of Alcalá)H-Index: 7
Last. Romuald Lepers (French Institute of Health and Medical Research)H-Index: 37
view all 5 authors...
Maximum oxygen consumption ($\dot{V}{\text{O}}_{{ 2 {\text{max}}}}) is not only an indicator of endurance performance, but also a strong predictor of cardiovascular disease and mortality. This physiological parameter is known to decrease with aging. In turn, physical exercise might attenuate the rate of aging-related decline in \dot{V}{\text{O}}_{{ 2 {\text{max}}}}, which in light of the global population aging is of major clinical relevance, especially at advanced ages. In this narrative...
2 CitationsSource
#1Giacomo Boffa (UniGe: University of Genoa)H-Index: 1
#2Nicolò Bruschi (UniGe: University of Genoa)
Last. Matilde Inglese (UniGe: University of Genoa)H-Index: 5
view all 9 authors...
The association between treatment-related lymphopenia in multiple sclerosis, drug efficacy and the risk of infections is not yet fully understood. The objective of this study was to assess whether lymphopenia is associated with short-term treatment response and infection rate in a real-life multiple sclerosis population treated with fingolimod and dimethyl-fumarate. We assessed the associations between baseline absolute lymphocyte count and the lymphocyte mean percentage decrease at 6 and 12 mon...
#1Zhiying JiaH-Index: 2
#2Lin Chen (Ha Tai: Xiamen University)H-Index: 7
Last. Peng Xu (Ha Tai: Xiamen University)H-Index: 51
view all 11 authors...
Abstract Koi herpesvirus is a double-stranded DNA virus that causes fatal disease and mortality in koi and common carp (Cyprinus carpio) of all ages. Koi herpesvirus disease has been added to the list of notifiable diseases of the World Organisation for Animal Health. The genetic basis of fish resistance to Koi herpesvirus remains little understood, and thus, it cannot be used in genetic breeding programs to produce high-resistance carp strains. Dissection of the molecular mechanism of resistanc...