scholarly journals Natural Killer Cells Regulate Pulmonary Macrophages Polarization in Host Defense Against Chlamydial Respiratory Infection

2022 ◽  
Vol 11 ◽  
Author(s):  
Lei Zhao ◽  
Jing Li ◽  
Xiaoqing Zhou ◽  
Qianqian Pan ◽  
Weiming Zhao ◽  
...  
Keyword(s):  
Nk Cells ◽  
Respiratory Infection ◽  
Host Defense ◽  
Chlamydial Infection ◽  
Macrophage Polarization ◽  
Bacterial Load ◽  
Lung Macrophages ◽  
M1 Polarization ◽  
Pulmonary Macrophages ◽  
Ifn Γ

NK cells and pulmonary macrophages both are important components of innate immunity. The interaction between NK cells and pulmonary macrophages during chlamydial infection is poorly understood. In this study, we explored the effect of NK cells on regulation of pulmonary macrophage function during chlamydial respiratory infection. We found that NK depletion led to polarization of pulmonary macrophages from M1 to M2 phenotype, and it is related to reduced miR-155 expression in lung macrophage. Using adoptive transfer approach, we found that the recipients receiving lung macrophages isolated from C. muridarum-infected NK-cell-depleted mice exhibited an increased bacterial load and severe inflammation in the lung upon chlamydial challenge infection when compared with the recipients of lung macrophages from infected isotype control antibody treated mice. Herein, the effects of NK cells on macrophage polarization were examined in vitro. We found that NK cells from chlamydial-infected mice (iNK) significantly induced M1 polarization compared to that from uninfected mice (uNK). Inhibition of miR-155 expression in macrophages reduced M1 polarization induced by iNK, while miR-155 over-expression enhanced it. Furthermore, neutralization of IFN-γ in the coculture system decreased the expression of miR-155 by macrophages, and resulted in weakened M1 polarization. The data indicates that NK cells promote M1 polarization through up-regulation of miR-155 in macrophages by producing IFN-γ during chlamydial infection, and NK-regulated macrophage polarization is functionally relevant to host defense against the infection.

scholarly journals Activation of HIF Signaling in Mononuclear Phagocyte System Causes Hemophagocytic Lymphohistiocytosis in C57/BL6 Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3675-3675
Author(s):  
Rui Huang ◽  
Yoshihiro Hayashi ◽  
Xiaomei Yan ◽  
Michael Jordan ◽  
Gang Huang
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Macrophage Polarization ◽  
Mononuclear Phagocyte ◽  
Mononuclear Phagocyte System ◽  
Cell Numbers ◽  
Ifn Γ

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by an overwhelming activation of diverse immune cells. Chemotherapy based regimen as a first-line therapy for HLH has a substantial risk of mortality. Thus, exploring a less toxic therapy is urgently needed. Accumulating evidence suggests that hypoxia-inducible factors (HIFs) play an important role in the regulation of the immune system. Hypoxia, as well as inflammation, infectious microorganisms, and cancer, triggers HIF expression and stabilization in immune cells. HIFs activation enhances phagocyte capacity, drives T cell differentiation and increases cytotoxic activity. HIFs also regulate the cellular metabolism of immune cells to dictate their fate, development, and function. However, little is known about HIFs' function in HLH pathogenesis. To determine whether activation of HIF-1α/HIF-1b in hematopoietic cells is sufficient to induce HLH phenotypes, we generated transgenic mice with doxycycline-inducible HIF-1α/HIF-1b expression. Using a Vav1-Cre/Rosa26-LSL-rtTA driver, a doxycycline-inducible expression of both a stable and constitutively active human HIF-1α triple-point-mutation (TPM) and wild-type HIF-1β was achieved. All the inducible HIF-1α/HIF-1b mice developed HLH phenotypes in C57/BL6background and died within three weeks. They quickly developed severe anemia, thrombocytopenia, multi-organ failure, splenomegaly, and hemophagocytosis. Total and type-1 polarized macrophages were significantly increased in the bone marrow (BM) and spleen (SP) of HLH mice compared to the controls. To determine the phagocytic activity of the type-1 polarized macrophages, we generated type-1 and type-2 polarized macrophages from BM mononuclear cells in vitro with M-CSF/IFNγ or M-CSF/IL-4 respectively. We found that type 1 rather than type 2 macrophages engulfed erythroblasts in an in vitro co-culture assay. IFN-γ signaling is critical for Type-1 macrophage polarization. We generated IFN-γ receptor-/- /Vav1-Cre/LSL/TPM mice and found that knockout of IFN-γ receptor completely blocked the macrophage activation and HLH development. Interestingly, the serum IFN-γ level was only slightly upregulated in Vav1-Cre/LSL/TPM mice, suggesting that IFN-γ locally, but not systemically, exerts its function in our HLH model. However IFN-γ expression in NK cells and CD8+ T cells did not increase. Thus, the source of the IFN-γ for macrophage polarization is still unclear. In primary HLH, defective cytotoxic function in NK and T cells is important for HLH development. We found that the cell surface CD107a (degranulation) and NK46p (activating receptor) expression didn't change in these HLH mice. Interestingly, the absolute numbers of total NK cells and DX5+ mature cytotoxic NK cells were significantly reduced in the PB, SP, and BM from HLH mice. However, the frequencies of CD8+ T cells, CD4+ T cells, Th17 cells, and total T cells did not change in HLH mice. In order to dissect the contribution of individual immune cell subpopulations to the HLH pathogenesis, diverse lineage specific Cre transgenic alleles were used. Induction of TPM allele in myeloid cells (LysM-Cre), mature T cells (dLck-Cre), NK cells (NCR-Cre), or multi-lineages (LysM-Cre/dLck-Cre) did not cause HLH. Interestingly, induction of TPM allele in the mononuclear phagocyte system (monocyte, macrophage, and dendritic cells) with Cx3cr1-Cre could give rise to HLH phenotypes, as well as macrophage activation and reduced NK cell numbers, which are similar to the Vav1-Cre model. These results indicate that activation of HIF-1α/HIF-1b in the mononuclear phagocyte system is sufficient to polarize macrophages and induce HLH phenotype. The reduced NK cell numbers may be secondary to macrophage/dendritic cell activation in this HLH model. In conclusion, we found that; 1) induction of stable and constitutively active form of HIF-1α/HIF-1β expression in hematopoietic cells, especially in the mononuclear phagocyte system, polarizes macrophages and causes HLH, 2) IFN-γ signaling is required for HLH development and macrophages/dendritic cells are critical immune cell populations in this model, 3) Reduced NK cell numbers may be a secondary phenomenon in this model. This new HLH model recapitulates the features of secondary HLH in human, provides a unique model for dissecting the detail mechanisms, and helps in testing new therapies for sHLH. Disclosures No relevant conflicts of interest to declare.

scholarly journals IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization

2018 ◽  
Author(s):  
Kyuho Kang ◽  
Sung Ho Park ◽  
Keunsoo Kang ◽  
Lionel B. Ivashkiv
Keyword(s):  
Histone Acetylation ◽  
Metabolic Pathways ◽  
Target Genes ◽  
Macrophage Polarization ◽  
Differential Regulation ◽  
Inflammatory Genes ◽  
Synergistic Activation ◽  
M1 Polarization ◽  
Combined Action ◽  
Ifn Γ

AbstractComplete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.

scholarly journals Differential Sensitivities of Chlamydia trachomatis Strains to Inhibitory Effects of Gamma Interferon

2000 ◽  
Vol 68 (10) ◽  
pp. 6038-6040 ◽  
Author(s):  
Richard P. Morrison
Keyword(s):  
Cell Culture ◽  
Host Defense ◽  
Culture System ◽  
Chlamydial Infection ◽  
Gamma Interferon ◽  
Cell Culture System ◽  
Inhibitory Effects ◽  
Ifn Γ ◽  
Important Cytokine

ABSTRACT Gamma interferon (IFN-γ) is an important cytokine in host defense against chlamydial infection. An in vitro cell culture system was used to show that IFN-γ inhibition of chlamydial growth, as determined by diminished recovery of infectious elementary bodies, differed markedly among chlamydial strains. These differences in sensitivity among chlamydial strains to IFN-γ-mediated inhibition may profoundly influence the clinical outcome of infection.

scholarly journals Valproic acid inhibits interferon-γ production by NK cells and increases susceptibility to Listeria monocytogenes infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rodolfo Soria-Castro ◽  
Alma D. Chávez-Blanco ◽  
Blanca Estela García-Pérez ◽  
Isabel Wong-Baeza ◽  
Raúl Flores-Mejía ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Listeria Monocytogenes ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Bacterial Load ◽  
Interferon Γ ◽  
Ifn Γ ◽  
Vitro Analysis

Abstract Valproic acid (VPA) is a drug commonly used for epileptic seizure control. Recently, it has been shown that VPA alters the activation of several immune cells, including Natural Killer (NK) cells, which play an important role in the containment of viruses and intracellular bacteria. Although VPA can increase susceptibility to extracellular pathogens, it is unknown whether the suppressor effect of VPA could affect the course of intracellular bacterial infection. This study aimed to evaluate the role of VPA during Listeria monocytogenes (L.m) infection, and whether NK cell activation was affected. We found that VPA significantly augmented mortality in L.m infected mice. This effect was associated with increased bacterial load in the spleen, liver, and blood. Concurrently, decreased levels of IFN-γ in serum and lower splenic indexes were observed. Moreover, in vitro analysis showed that VPA treatment decreased the frequency of IFN-γ-producing NK cells within L.m infected splenocytes. Similarly, VPA inhibited the production of IFN-γ by NK cells stimulated with IL-12 and IL-18, which is a crucial system for early IFN-γ production in listeriosis. Finally, VPA decreased the phosphorylation of STAT4, p65, and p38, without affecting the expression of IL-12 and IL-18 receptors. Altogether, our results indicate that VPA increases the susceptibility to Listeria monocytogenes infection and suggest that NK cell is one of the main targets of VPA, but further work is needed to ascertain this effect.

“M1 macrophage polarization prevails in EBV infected children in an immuneregulatory environment”

2021 ◽  
Author(s):  
A. Moyano ◽  
N. M. Ferressini Gerpe ◽  
E. De Matteo ◽  
M. V. Preciado ◽  
P. Chabay
Keyword(s):  
Persistent Infection ◽  
Primary Infection ◽  
Macrophage Polarization ◽  
Inverse Correlation ◽  
Developed Countries ◽  
Macrophage Response ◽  
M1 Polarization ◽  
M1 Macrophage ◽  
Ifn Γ ◽  
Anti Inflammatory

Macrophages can be polarized toward a proinflammatory phenotype (M1) (CD68+) or to an anti-inflammatory one (M2) (CD163+). Polarization can be triggered by cytokines such as IFN-γ for M1, or IL-10 and TGF-β, for M2. In the context of pediatric EBV infection, little is known about macrophage polarization in EBV primary or persistent infection. When studying tonsils of patients undergoing primary infection (PI), healthy carrier (HC), reactivation (R) and not infected (NI), M1 profile prevailed in all infection status. However, an increase in M2 cells was observed in those patients with broader expression of latency antigens, in particular EBNA2. Tonsils from primary infected patients showed an increased IL-10 expression, whereas, unexpectedly, TGF-β expression correlated with M1 marker. Furthermore, an inverse correlation was demonstrated between CD68 and IFN-γ. Therefore, in the context of asymptomatic infection in children, M1 macrophage polarization prevails, even in the presence of IL-10 and TGF-ꞵ immunomodulatory cytokines, and it might be independent from lymphomagenesis process. Our finding indicates that macrophages may have a significant plasticity in response to different types of extrinsic stimuli, and further studies are required to investigate M1 polarization under anti-inflammatory stimuli. Importance Most studies on EBV primary infection have been performed in adolescents and young adult populations with Infectious Mononucleosis (IM) in developed countries. Furthermore, studies related to macrophage polarization were assessed in EBV-associated lymphomas, but little is known about macrophage polarization in the context of primary infection at the site of viral entry and replication, the tonsils. Therefore, the aim of this study was to characterize macrophage response in children undergoing EBV primary or persistent infection, in order to enlighten the role of macrophages in viral pathogenesis, in a population with a high incidence of EBV-associated lymphomas in children younger than 10 years old. This study may contribute to explain, at least in part, the asymptomatic viral infection in children from an underdeveloped region, since M1 polarization pattern prevails, but in a regulatory environment.

Characterization and functional analysis of novel circulating NK cell sub-populations

2019 ◽  
Vol 31 (8) ◽  
pp. 515-530
Author(s):  
Saichit Khummuang ◽  
Kantinan Chuensirikulchai ◽  
Supansa Pata ◽  
Witida Laopajon ◽  
Nuttapol Chruewkamlow ◽  
...  
Keyword(s):  
Nk Cells ◽  
Host Defense ◽  
Cell Biology ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Cytolytic Function ◽  
Tnf Α ◽  
Microbial Infections ◽  
Ifn Γ ◽  
Nk Cell Therapy

Abstract Natural killer (NK) cells are innate lymphoid cells having potent cytolytic function that provide host defense against microbial infections and tumors. Using our generated monoclonal antibody (mAb), named FE-1H10, new NK cell sub-populations in peripheral blood were identified. The molecules recognized by mAb FE-1H10 were expressed on a sub-population of CD3−CD56dim NK cells. The epitope recognized by mAb FE-1H10 was demonstrated to be N-glycan and proven to be different from CD57. Upon K562 stimulation, the CD56dimFE-1H10+ NK cell sub-population exhibited significantly lower cytolytic function with low ability to degranulate and release cytolytic granules compared to the CD56dimFE-1H10− NK cell sub-population. Moreover, the CD56dimFE-1H10+ NK cells produced less IFN-γ and TNF-α than the CD56dimFE-1H10− NK cells. We demonstrated here that mAb FE-1H10 could identify two sub-populations of circulating CD56dim NK cells with different functions. Our discovery of new sub-populations of NK cells improves our understanding of NK cell biology and may lead to the development of new approaches for NK cell therapy.

scholarly journals Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease

2007 ◽  
Vol 82 (6) ◽  
pp. 3021-3030 ◽  
Author(s):  
Kevin B. Walsh ◽  
Melissa B. Lodoen ◽  
Robert A. Edwards ◽  
Lewis L. Lanier ◽  
Thomas E. Lane
Keyword(s):  
Liver Disease ◽  
Immune Responses ◽  
Host Defense ◽  
Nk Cell ◽  
Hepatitis Virus ◽  
Innate Immune ◽  
Liver Pathology ◽  
Innate Immune Responses ◽  
Ifn Γ ◽  
The Brain

ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

scholarly journals POS0333 ALTERED MACROPHAGE POLARIZATION PHENOTYPES IN SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 394.1-394
Author(s):  
A. Hukara ◽  
M. Rudnik ◽  
C. B. Rufer ◽  
O. Distler ◽  
P. Blyszczuk ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Macrophage Polarization ◽  
Peritoneal Macrophages ◽  
Surface Marker ◽  
Surface Marker Expression ◽  
Tnf Α ◽  
Ifn Γ ◽  
Alternatively Activated ◽  
Classically Activated

Background:Fos-like 2 (Fosl-2) is a transcription factor of the AP-1 family and has a broad range in inducing cellular changes affecting fibrosis and inflammatory responses. Pathological effects of Fosl-2 have been associated with systemic sclerosis (SSc). In addition, increased expression of Fosl-2 has been detected in human SSc monocyte-derived macrophages [1]. Monocytes and macrophages play a central role in activating and propagating acute inflammation followed by pathological fibrosis and organ dysfunction. The classification of the macrophage polarization phenotype can be assigned based on the stimulus, for example into classically-activated M(LPS), and alternatively-activated M(IL-4) macrophages [2]. However, the role of the Fosl-2 transcription factor in macrophage polarization remains elusive.Objectives:To investigate the role of Fosl-2 in macrophage polarization in SSc using Fosl-2 overexpressing transgenic (Fosl-2 tg) mice and human blood-derived macrophages from SSc patients.Methods:Thiogylcolate-elicited peritoneal macrophages were isolated from wild-type (wt) and Fosl-2 tg mice. Human peripheral CD14+ blood-derived monocytes were isolated and differentiated to macrophages (hMDM) from healthy controls and SSc patients. Murine and human macrophages were polarized with LPS (10 ng/ml), LPS + recombinant mouse IFN-γ (10 ng/ml), recombinant mouse, resp. human IL-4 (10 ng/ml) or remained untreated. Macrophage surface marker expression was assessed by flow cytometry using a mouse (F4/80, CD11b, CD86, CD80, CD38, MHCII, CD206, PD-L1, PD-L2, CD36) or human (CD38, CD40, CD86, PD-L2, PD-L1, CD163, CD206) designed polarization panel. Phagocytic activity was detected with pHrodo Red E.coli particles by flow cytometry. Gene expression and secretion of pro- and anti-inflammatory markers were measured by RT-qPCR, standard ELISAs and Griess Assay for nitric oxide production.Results:After LPS stimulation, mRNA levels of IL-1β (p<0.01, n=11-12), TNF-α (p=0.05, n=11-12) and IFN-γ (p<0.05, n=7) were reduced, whereas expression of IL-10 (p<0.05, n=11-12) was enhanced in Fosl-2 tg peritoneal macrophages in comparison to wt cells. Secretion of TNF-α (p<0.01, n=9-11) and nitric oxide (p<0.01, n=9) was impaired in Fosl-2 tg peritoneal macrophages compared to wt cells after LPS stimulation. Peritoneal macrophages were analyzed directly after isolation for macrophage polarization cell surface marker expression. Fosl-2 tg peritoneal macrophages showed an increase in the F4/80+CD11b+PD-L2+CD36+ cell population (p<0.01, n=3-6) compared to peritoneal macrophages from wt mice.The expression of cell surface markers of non-polarized and IL-4 stimulated SSc hMDM (n=17) showed an increased percentage of CD40+CD86+CD206+PD-L2+CD163+ cells (p<0.05) compared to healthy control hMDM (n=7). Phagocytic activity was enhanced in SSc hMDM (n=7) compared to healthy untreated (p<0.05), LPS (p=0.05) and IL-4 (p<0.05) hMDM (n=5).Conclusion:Our animal data indicates a role of Fosl-2 in regulating macrophage polarization with a shift from a classically-activated to an alternatively-activated phenotype. Similarly, SSc hMDM resemble a functional M(IL-4) alternative macrophage phenotype.Thus, maintaining a balanced proportion of classically- and alternatively-activated macrophage phenotypes may be an effective tool to control macrophage function in SSc.References:[1]Moreno-Moral, A., et al., Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk. Ann Rheum Dis, 2018. 77(4): p. 596-601.[2]Kania, G., M. Rudnik, and O. Distler, Involvement of the myeloid cell compartment in fibrogenesis and systemic sclerosis. Nat Rev Rheumatol, 2019. 15(5): p. 288-302.Disclosure of Interests:Amela Hukara: None declared, Michal Rudnik: None declared, Chantal Brigitta Rufer: None declared, Oliver Distler Speakers bureau: Actelion, Bayer, Boehringer Ingelheim, Medscape, Novartis, Roche, Menarini, Mepha, MSD, iQone, Pfizer, Consultant of: Abbvie, Actelion, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, ChemomAb, Corpuspharma, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, Kymera, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi, UCB, Lilly, Target BioScience, Pfizer, Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, Kymera Therapeutics, Mitsubishi Tanabe, Przemyslaw Blyszczuk: None declared, Gabriela Kania: None declared

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