Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses

2022 ◽  
Author(s):  
Youxiang Mao ◽  
Di Shi ◽  
Gen Li ◽  
Peng Jiang
Keyword(s):  
Immune Responses ◽  
Macrophage Activation

scholarly journals SLAMF7 engagement super-activates macrophages in acute and chronic inflammation

2020 ◽  
Author(s):  
Daimon P. Simmons ◽  
Hung N. Nguyen ◽  
Emma Gomez-Rivas ◽  
Yunju Jeong ◽  
Antonia F. Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Responses ◽  
Inflammatory Cytokine ◽  
Macrophage Activation ◽  
Rna Seq ◽  
Autocrine Signaling ◽  
Tnf Α ◽  
Activated Macrophage ◽  
Ifn Γ ◽  
Acute And Chronic Inflammation

AbstractMacrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a super-activated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression. Engaging this receptor drove an exuberant wave of inflammatory cytokine expression, and induction of TNF-α following SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients, but in gut macrophages from active Crohn’s disease patients and lung macrophages from severe COVID-19 patients. This suggests a central role for SLAMF7 in macrophage super-activation with broad implications in pathology.

scholarly journals MGL1 Receptor Plays a Key Role in the Control of T. cruzi Infection by Increasing Macrophage Activation through Modulation of ERK1/2, c-Jun, NF-κB and NLRP3 Pathways

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 108
Author(s):  
Tonathiu Rodriguez ◽  
Thalia Pacheco-Fernández ◽  
Alicia Vázquez-Mendoza ◽  
Oscar Nieto-Yañez ◽  
Imelda Juárez-Avelar ◽  
...  
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Cell Activation ◽  
Wild Type ◽  
Mhc Ii ◽  
Adaptive Immune ◽  
Splenic Cell ◽  
Tnf Α ◽  
Cruzi Infection

Macrophage galactose-C type lectin (MGL)1 receptor is involved in the recognition of Trypanosoma cruzi (T. cruzi) parasites and is important for the modulation of the innate and adaptive immune responses. However, the mechanism by which MGL1 promotes resistance to T. cruzi remains unclear. Here, we show that MGL1 knockout macrophages (MGL1−/− Mφ) infected in vitro with T. cruzi were heavily parasitized and showed decreased levels of reactive oxygen species (ROS), nitric oxide (NO), IL-12 and TNF-α compared to wild-type macrophages (WT Mφ). MGL1−/− Mφ stimulated in vitro with T. cruzi antigen (TcAg) showed low expression of TLR-2, TLR-4 and MHC-II, which resulted in deficient splenic cell activation compared with similar co-cultured WT Mφ. Importantly, the activation of p-ERK1/2, p-c-Jun and p-NF-κB p65 were significantly reduced in MGL1−/− Mφ exposed to TcAg. Similarly, procaspase 1, caspase 1 and NLRP3 inflammasome also displayed a reduced expression that was associated with low IL-β production. Our data reveal a previously unappreciated role for MGL1 in Mφ activation through the modulation of ERK1/2, c-Jun, NF-κB and NLRP3 signaling pathways, and to the development of protective innate immunity against experimental T. cruzi infection.

scholarly journals COVID-19 and HIV-Associated Immune Reconstitution Inflammatory Syndrome: Emergence of Pathogen-Specific Immune Responses Adding Fuel to the Fire

2021 ◽  
Vol 12 ◽  
Author(s):  
Nabila Seddiki ◽  
Martyn French
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Macrophage Activation ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
B Cell Differentiation ◽  
Adaptive Immune ◽  
Inflammatory Syndrome

Both coronavirus disease 2019 (COVID-19) and mycobacterial immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-1 infection result from immunopathology that is characterized by increased production of multiple pro-inflammatory chemokines and cytokines associated with activation of myeloid cells (monocytes, macrophages and neutrophils). We propose that both conditions arise because innate immune responses generated in the absence of effective adaptive immune responses lead to monocyte/macrophage activation that is amplified by the emergence of a pathogen-specific adaptive immune response skewed towards monocyte/macrophage activating activity by the immunomodulatory effects of cytokines produced during the innate response, particularly interleukin-18. In mycobacterial IRIS, that disease-enhancing immune response is dominated by a Th1 CD4+ T cell response against mycobacterial antigens. By analogy, it is proposed that in severe COVID-19, amplification of monocyte/macrophage activation results from the effects of a SARS-CoV-2 spike protein antibody response with pro-inflammatory characteristics, including high proportions of IgG3 and IgA2 antibodies and afucosylation of IgG1 antibodies, that arises from B cell differentiation in an extra-follicular pathway promoted by activation of mucosa-associated invariant T cells. We suggest that therapy for the hyperinflammation underlying both COVID-19 and mycobacterial IRIS might be improved by targeting the immunomodulatory as well as the pro-inflammatory effects of the ‘cytokine storm’.

scholarly journals Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tao Yu ◽  
Shucheng Gan ◽  
Qingchen Zhu ◽  
Dongfang Dai ◽  
Ni Li ◽  
...  
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Regulatory Mechanism ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Creb Binding Protein ◽  
Human Macrophages ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
Negative Regulatory Mechanism

Abstract Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.

TNF-α and IL-6: The Link between Immune and Bone System

2020 ◽  
Vol 21 (3) ◽  
pp. 213-227 ◽  
Author(s):  
Tiantian Wang ◽  
Chengqi He
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Bone Diseases ◽  
Necrosis Factor Alpha ◽  
Immune Mediated ◽  
Pathogenic Factors ◽  
Tnf Α ◽  
Proliferation And Differentiation ◽  
Factor Alpha ◽  
Necrosis Factor

Osteoimmunology is a new subject which focuses on the communication between the immune and the skeletal systems. Both the immune system and bone communicate with each other. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) play important roles in immune responses and bone metabolism. TNF-α and IL-6 enhance macrophage activation and antigen presentation, as well as regulating immunity through different mechanisms. A variety of groups have reported that TNF-α suppresses osteoblasts activity at some stages of differentiation and stimulates osteoclast proliferation and differentiation. In contrast, IL-6 mediates the actions of osteoblasts and osteoclasts through sophisticated mechanisms, which reflect dual effects. Both TNF-α and IL-6 can mediate the activity of osteocytes. Furthermore, both TNF-α and IL-6 are important pathogenic factors related to immune-mediated bone diseases including rheumatoid arthritis and postmenopausal osteoporosis. This review will discuss the contradictory findings concerning TNF-α and IL-6 in osteoimmunology and their potential for clinical application.

scholarly journals Tumor-Treating Fields Induce RAW264.7 Macrophage Activation Via NK-κB/MAPK Signaling Pathways

2019 ◽  
Vol 18 ◽  
pp. 153303381986822 ◽  
Author(s):  
Jeong-In Park ◽  
Kyung-Hee Song ◽  
Seung-Youn Jung ◽  
Jiyeon Ahn ◽  
Sang-Gu Hwang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Viability ◽  
Messenger Rna ◽  
Macrophage Activation ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Tumor Treating Fields

Objective: Tumor-treating fields are currently used to successfully treat various cancers; however, the specific pathways associated with its efficacy remain unknown in the immune responses. Here, we evaluated tumor-treating fields–mediated initiation of the macrophage-specific immune response. Materials and Methods: We subjected RAW 264.7 mouse macrophages to clinically relevant levels of tumor-treating fields (0.9 V/cm, 150 kHz) and evaluated alterations in cytokine expression and release, as well as cell viability. Additionally, we investigated the status of immunomodulatory pathways to determine their roles in tumor-treating fields–mediated immune activation. Results and Discussion: Our results indicated that tumor-treating fields treatment at 0.9 V/cm decreased cell viability and increased cytokine messenger RNA/protein levels, as well as levels of nitric oxide and reactive oxygen species, relative to controls. The levels of tumor necrosis factor α, interleukin 1β, and interleukin 6 were markedly increased in tumor-treating fields–treated RAW 264.7 cells cocultured with 4T1 murine mammary carcinoma cells compared with those in 4T1 or RAW 264.7 cells with or without tumor-treating fields treatment. Moreover, the viability of 4T1 cells treated with the conditioned medium of tumor-treating fields–stimulated RAW 264.7 cells decreased, indicating that macrophage activation by tumor-treating fields effectively killed the tumor cells. Moreover, tumor-treating fields treatment activated the nuclear factor κB and mitogen-activated protein kinase pathways involved in immunomodulatory signaling. Conclusion: These results provide critical insights into the mechanisms through which tumor-treating fields affect macrophage-specific immune responses and the efficacy of this method for cancer treatment.

scholarly journals Precision N-Glycoproteomic Profiling of Murine Peritoneal Macrophages After Different Stimulations

2021 ◽  
Vol 12 ◽  
Author(s):  
Lujie Yang ◽  
Tianqi Gong ◽  
Huali Shen ◽  
Jiangnan Pei ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Biological Processes ◽  
Toll Like Receptor ◽  
Adaptive Immune ◽  
Murine Peritoneal Macrophages ◽  
Molecular Patterns ◽  
Stimulation Of

Macrophages are important immune cells that participate in both innate and adaptive immune responses, such as phagocytosis, recognition of molecular patterns, and activation of the immune response. In this study, murine peritoneal macrophages were isolated and then activated by LPS, HSV and VSV. Integrative proteomic and precision N-glycoproteomic profiling were conducted to assess the underlying macrophage activation. We identified a total of 587 glycoproteins, including 1239 glycopeptides, 526 monosaccharide components, and 8326 intact glycopeptides in glycoproteomics, as well as a total of 4496 proteins identified in proteomic analysis. These glycoproteins are widely involved in important biological processes, such as antigen presentation, cytokine production and glycosylation progression. Under the stimulation of the different pathogens, glycoproteins showed a dramatic change. We found that receptors in the Toll-like receptor pathway, such as Tlr2 and CD14, were increased under LPS and HSV stimulation. Glycosylation of those proteins was proven to influence their subcellular locations.

scholarly journals Paired Activating and Inhibitory Immunoglobulin-like Receptors, MAIR-I and MAIR-II, Regulate Mast Cell and Macrophage Activation

2003 ◽  
Vol 198 (2) ◽  
pp. 223-233 ◽  
Author(s):  
Katsumi Yotsumoto ◽  
Yasushi Okoshi ◽  
Kazuko Shibuya ◽  
Satoshi Yamazaki ◽  
Satoko Tahara-Hanaoka ◽  
...  
Keyword(s):  
Mast Cells ◽  
Immune Responses ◽  
Macrophage Activation ◽  
Peritoneal Macrophages ◽  
The Other ◽  
Surface Receptors ◽  
Inhibitory Cell ◽  
Sorting Motif ◽  
Ige Mediated ◽  
Activation Motif

Immune responses are regulated by opposing positive and negative signals triggered by the interaction of activating and inhibitory cell surface receptors with their ligands. Here, we describe novel paired activating and inhibitory immunoglobulin-like receptors, designated myeloid-associated immunoglobulin-like receptor (MAIR) I and MAIR-II, whose extracellular domains are highly conserved by each other. MAIR-I, expressed on the majority of myeloid cells, including macrophages, granulocytes, mast cells, and dendritic cells, contains the tyrosine-based sorting motif and the immunoreceptor tyrosine-based inhibitory motif-like sequences in the cytoplasmic domain and mediates endocytosis of the receptor and inhibition of IgE-mediated degranulation from mast cells. On the other hand, MAIR-II, expressed on subsets of peritoneal macrophages and B cells, associates with the immunoreceptor tyrosine-based activation motif-bearing adaptor DAP12 and stimulates proinflammatory cytokines and chemokine secretions from macrophages. Thus, MAIR-I and MAIR-II play important regulatory roles in cell signaling and immune responses.

scholarly journals Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies

Science ◽  
2013 ◽  
Vol 341 (6141) ◽  
pp. 88-91 ◽  
Author(s):  
Kipp Weiskopf ◽  
Aaron M. Ring ◽  
Chia Chi M. Ho ◽  
Jens-Peter Volkmer ◽  
Aron M. Levin ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Immune Responses ◽  
Cancer Cells ◽  
Macrophage Activation ◽  
Universal Method ◽  
Wild Type ◽  
High Affinity ◽  
Macrophage Phagocytosis

CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This “one-two punch” directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.

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