scholarly journals TLR9-mediated inflammation drives a Ccr2-independent peripheral monocytosis through enhanced extramedullary monocytopoiesis

2016 ◽  
Vol 113 (39) ◽  
pp. 10944-10949 ◽  
Author(s):  
Lehn K. Weaver ◽  
Niansheng Chu ◽  
Edward M. Behrens
Keyword(s):  
Autoimmune Diseases ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Wild Type ◽  
Persistent Inflammation ◽  
The Face ◽  
Independent Expansion ◽  
Responsive Cell

Monocytes are innate immune cells that interact with their environment through the expression of pattern recognition receptors, including Toll-like receptors (TLRs). Both monocytes and TLRs are implicated in driving persistent inflammation in autoimmune diseases. However, cell-intrinsic mechanisms to control inflammation, including TLR tolerance, are thought to limit inflammatory responses in the face of repeated TLR activation, leaving it unclear how chronic TLR-mediated inflammation is maintained in vivo. Herein, we used a well-characterized model of systemic inflammation to determine the mechanisms allowing sustained TLR9 responses to develop in vivo. Monocytes were identified as the main TLR9-responsive cell and accumulated in peripherally inflamed tissues during TLR9-driven inflammation. Intriguingly, canonical mechanisms controlling monocyte production and localization were altered during the systemic inflammatory response, as accumulation of monocytes in the liver and spleen developed in the absence of dramatic increases in bone marrow monocyte progenitors and was independent of chemokine (C-C motif) receptor 2 (Ccr2). Instead, TLR9-driven inflammation induced a Ccr2-independent expansion of functionally enhanced extramedullary myeloid progenitors that correlated with the peripheral accumulation of monocytes in both wild-type and Ccr2−/− mice. Our data implicate inflammation-induced extramedullary monocytopoiesis as a peripheral source of newly produced TLR9 responsive monocytes capable of sustaining chronic TLR9 responses in vivo. These findings help to explain how chronic TLR-mediated inflammation may be perpetuated in autoimmune diseases and increase our understanding of how monocytes are produced and positioned during systemic inflammatory responses.

scholarly journals MyD88-Dependent Signaling Affects the Development of Meningococcal Sepsis by Nonlipooligosaccharide Ligands

2006 ◽  
Vol 74 (6) ◽  
pp. 3538-3546 ◽  
Author(s):  
Laura Plant ◽  
Hong Wan ◽  
Ann-Beth Jonsson
Keyword(s):  
Inflammatory Responses ◽  
Innate Immune ◽  
Meningococcal Sepsis ◽  
Wild Type ◽  
Microbial Infections ◽  
In The Wild ◽  
Myeloid Differentiation Factor ◽  
Dependent Pathway ◽  
Meningococcal Strain

ABSTRACT The Toll-like receptors (TLRs) and the adaptor myeloid differentiation factor 88 (MyD88) are important in the innate immune defenses of the host to microbial infections. Meningococcal ligands signaling via TLRs control inflammatory responses, and stimulation can result in fulminant meningococcal sepsis. In this study, we show that the responses to nonlipooligosaccharide (non-LOS) ligands of meningococci are MyD88 dependent. An isogenic LOS-deficient mutant of the serogroup C meningococcal strain FAM20 caused fatal disease in wild type C57BL/6 mice that was not observed in MyD88−/− mice. Fatality correlated with high proinflammatory cytokine and C5a levels in serum, high neutrophil numbers in blood, and increased bacteremia at 24 h postinfection in the wild-type mice. Infection with the parent strain FAM20 resulted in fatality in 100% of the wild-type mice and 50% of the MyD88−/− mice. We conclude that both LOS and another neisserial ligand cause meningococcal sepsis in an in vivo mouse model and confirm that meningococcal LOS can act via both the MyD88- dependent and -independent pathways, while the non-LOS meningococcal ligand(s) acts only via the MyD88-dependent pathway.

scholarly journals GABA transporter sustains IL-1β production in macrophages

2021 ◽  
Vol 7 (15) ◽  
pp. eabe9274
Author(s):  
Yaoyao Xia ◽  
Fang He ◽  
Xiaoyan Wu ◽  
Bie Tan ◽  
Siyuan Chen ◽  
...  
Keyword(s):  
Immune Responses ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
High Fat ◽  
Gaba Transporter ◽  
Host Immune Responses ◽  
Diet Induced Obesity

Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3–ASC–caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

scholarly journals LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils

2021 ◽  
Vol 22 (18) ◽  
pp. 9803
Author(s):  
Trim Lajqi ◽  
Maylis Braun ◽  
Simon Alexander Kranig ◽  
David Frommhold ◽  
Johannes Pöschl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
In Vivo Studies ◽  
Mouse Bone Marrow ◽  
Innate Immune Cells ◽  
Trained Immunity

A growing body of evidence suggests that innate immune cells can respond in a memory-like (adaptive) fashion, which is referred to as trained immunity. Only few in vivo studies have shown training effects in neutrophils; however, no in vitro setup has been established to study the induction of trained immunity or tolerance in neutrophils by microbial agents. In light of their short lifespan (up to 48 h), we suggest to use the term trained sensitivity for neutrophils in an in vitro setting. Here, we firstly describe a feasible two-hit model, using different doses of lipopolysaccharide (LPS) in bone marrow neutrophils. We found that low doses (10 pg/mL) induce pro-inflammatory activation (trained sensitivity), whereas priming with high doses (100 ng/mL) leads to suppression of pro-inflammatory mediators such as TNF-α or IL-6 (tolerance) (p < 0.05). On a functional level, trained neutrophils displayed increased phagocytic activity and LFA-1 expression as well as migrational capacity and CD11a expression, whereas tolerant neutrophils show contrasting effects in vitro. Mechanistically, TLR4/MyD88/PI3Ks regulate the activation of p65, which controls memory-like responses in mouse bone marrow neutrophils (p < 0.05). Our results open a new window for further in vitro studies on memory-like inflammatory responses of short-lived innate immune cells such as neutrophils.

scholarly journals Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

2020 ◽  
Author(s):  
Abigail Elliot ◽  
Henna Myllymäki ◽  
Yi Feng
Keyword(s):  
Immune Cells ◽  
Cancer Biology ◽  
Inflammatory Responses ◽  
Live Imaging ◽  
Innate Immune ◽  
Leukocyte Recruitment ◽  
Innate Immune Cells ◽  
Neoplastic Cells ◽  
Tumour Development ◽  
Tumour Initiation

The zebrafish is now an important model organism for cancer biology studies and provides some unique and complementary opportunities in comparison to the mammalian equivalent. The translucency of zebrafish has allowed in vivo live imaging studies of tumour initiation and progression at the cellular level thus providing novel insights into our understanding of cancer. Here we summarise and discuss available transgenic zebrafish tumour models and what we have gleaned from them with respect to cancer inflammation. In particular, we focus on the host inflammatory response toward transformed cells during the pre-neoplastic stage of tumour development. We discuss features of tumour associated macrophages and neutrophils in mammalian models and present evidence which supports the idea that these inflammatory cells promote early stage tumour development and progression. Direct live imaging of tumour initiation in zebrafish models has shown that the intrinsic inflammation induced by pre-neoplastic cells is tumour promoting. Signals mediating leukocyte recruitment to pre-neoplastic cells in zebrafish correspond to signals mediating leukocyte recruitment in mammalian tumours. The activation state of macrophages and neutrophils recruited to pre-neoplastic cells appears to be heterogenous, as seen in mammalian models, which provides an opportunity to study the plasticity of innate immune cells during tumour initiation. Although several potential mechanisms are described that might mediate the trophic function of innate immune cells during tumour initiation in zebrafish, there are several unknowns that are yet to be resolved. Rapid advancement of genetic tools and imaging technologies for zebrafish will facilitate research into the mechanisms that modulate leukocyte function during tumour initiation and identify targets for cancer prevention.

scholarly journals Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1018 ◽  
Author(s):  
Abigail Elliot ◽  
Henna Myllymäki ◽  
Yi Feng
Keyword(s):  
Immune Cells ◽  
Cancer Biology ◽  
Inflammatory Responses ◽  
Live Imaging ◽  
Innate Immune ◽  
Leukocyte Recruitment ◽  
Innate Immune Cells ◽  
Neoplastic Cells ◽  
Tumour Development ◽  
Tumour Initiation

The zebrafish is now an important model organism for cancer biology studies and provides unique and complementary opportunities in comparison to the mammalian equivalent. The translucency of zebrafish has allowed in vivo live imaging studies of tumour initiation and progression at the cellular level, providing novel insights into our understanding of cancer. Here we summarise the available transgenic zebrafish tumour models and discuss what we have gleaned from them with respect to cancer inflammation. In particular, we focus on the host inflammatory response towards transformed cells during the pre-neoplastic stage of tumour development. We discuss features of tumour-associated macrophages and neutrophils in mammalian models and present evidence that supports the idea that these inflammatory cells promote early stage tumour development and progression. Direct live imaging of tumour initiation in zebrafish models has shown that the intrinsic inflammation induced by pre-neoplastic cells is tumour promoting. Signals mediating leukocyte recruitment to pre-neoplastic cells in zebrafish correspond to the signals that mediate leukocyte recruitment in mammalian tumours. The activation state of macrophages and neutrophils recruited to pre-neoplastic cells in zebrafish appears to be heterogenous, as seen in mammalian models, which provides an opportunity to study the plasticity of innate immune cells during tumour initiation. Although several potential mechanisms are described that might mediate the trophic function of innate immune cells during tumour initiation in zebrafish, there are several unknowns that are yet to be resolved. Rapid advancement of genetic tools and imaging technologies for zebrafish will facilitate research into the mechanisms that modulate leukocyte function during tumour initiation and identify targets for cancer prevention.

scholarly journals Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans

2018 ◽  
Vol 104 (4) ◽  
pp. 1187-1199 ◽  
Author(s):  
Ahmed Iqbal ◽  
Lynne R Prince ◽  
Peter Novodvorsky ◽  
Alan Bernjak ◽  
Mark R Thomas ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Immune System ◽  
Innate Immune System ◽  
Low Dose ◽  
Inflammatory Responses ◽  
Platelet Reactivity ◽  
Innate Immune ◽  
Endotoxin Challenge ◽  
Intermediate Monocytes

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P &lt; 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P &lt; 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P &lt; 0.01; vs sham-saline 26.20 ± 3.86/μL, P &lt; 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P &lt; 0.001; vs sham-saline 19.05 ± 3.81/μL, P &lt; 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P &lt; 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P &lt; 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P &lt; 0.05; vs sham-saline 3.81± 1.42/μL, P &lt; 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P &lt; 0.01; vs sham-saline 3.08 ± 1.01/μL, P &lt; 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P &lt; 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

Calreticulin Promotes Immunity Against Acute Myeloid Leukemia Cells in Vivo

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 996-996
Author(s):  
Xiufen Chen ◽  
Dominick Fosco ◽  
Douglas E. Kline ◽  
Justin Kline
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Surface ◽  
Vector Control ◽  
Immune Cells ◽  
Myeloid Leukemia ◽  
Innate Immune ◽  
Innate Immune Cells

Abstract Pre-apoptotic cancer cells release internalized calreticulin (CRT) to their surface prior to death, which acts as an ‘eat-me’ signal to local phagocytes. Chemotherapy and irradiation, which can induce immunogenic cell death through CRT translocation, can also result in local and/or systemic immune suppression in the host. To bypass the requirement of exposing the host to chemotherapy to induce translocation of CRT to the cell surface, murine acute myeloid leukemia (AML) cells (C1498), were engineered to constitutively express cell surface CRT (C1498.CRT). Vector control C1498 or C1498.CRT cells were inoculated intravenously (IV) into C57BL/6 mice. Significantly prolonged survival was observed in hosts harboring C1498.CRT versus vector control C1498 cells systemically. The survival benefit were abrogated in both Rag2-/- hosts or by depletion of T cells with anti-CD4 plus anti-CD8 antibodies, arguing that the immune-mediated effect of cell-surface CRT expression is dependent upon a functional adaptive immune system. More strikingly, systemic inoculation with C1498.CRT cells expressing the model SIYRYYGL (SIY) peptide antigen (C1498.SIY.CRT cells) resulted in almost complete protection from AML development (>90% long term survival vs. 10% of C1498.SIY vector control cells). All animals surviving a primary C1498.SIY.CRT challenge rejected a subsequent re-challenge with C1498.SIY cells, suggesting that CRT-expressing AML cells promote immunologic memory. Significantly enhanced expansion and unregulated IFNγ production were observed among SIY-specific T cell receptor transgenic CD8+ 2C T cells following their adoptive transfer into hosts bearing C1498.SIY.CRT AML cells versus vector control C1498.SIY cells. Interestingly, CRT expression on AML cells did not promote their in vivo phagocytosis by innate immune cells, specifically splenic CD8a+ dendritic cells known to engulf AML cells following their IV inoculation. IL-12 production by CD8α+CD11c+ dendritic cells which had engulfed C1498 and C1498.CRT cells in vivo was similarly induced, and cross-presentation of the SIY antigen to 2C T cells ex vivo by purified CD8a+DCs following in vivo exposure to C1498.SIY or C1498.SIY.CRT cells was also similar. In conclusion, it is clear that expression on CRT on the surface of AML cells leads to robust leukemia-specific T cell activation and expansion resulting in prolonged leukemia-specific survival in AML-bearing animals. Although a direct effect of CRT on innate immune cells, such as dendritic cells, is suspected, the molecular mechanism underlying the “CRT effect” remains unclear, and is being explored further through gene expression analysis in purified DCs which have engulfed CRT-expressing or control AML cells in vivo, as well as in animals genetically deficient in the putative CRT receptor, LRP, in dendritic cells. It will be of interest to analyze spontaneous CRT expression on AML cells from human samples and to correlate cell surface CRT expression with the presence or absence of spontaneous T cell responses to known AML antigens and with clinical outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

2018 ◽  
Author(s):  
Carlos R. Figueiredo ◽  
Ricardo A. Azevedo ◽  
Sasha Mousdell ◽  
Pedro T. Resende-Lara ◽  
Lucy Ireland ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Metastatic Melanoma ◽  
Immune Cells ◽  
Tumour Microenvironment ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Adaptive Immune Cells ◽  
Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

scholarly journals Therapies Targeting Trained Immune Cells in Inflammatory and Autoimmune Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Cristina Municio ◽  
Gabriel Criado
Keyword(s):  
Autoimmune Diseases ◽  
Immune Cells ◽  
Inflammatory Diseases ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Epigenetic Reprogramming ◽  
Innate Immune Cells ◽  
Tissue Destruction ◽  
Specific Stimulus ◽  
Trained Immunity

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.

scholarly journals There's Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

2018 ◽  
Author(s):  
Joseph W. Jackson ◽  
Tim Sparer
Keyword(s):  
Recent Literature ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Free Virus ◽  
Cmv Infection ◽  
Viral Dissemination ◽  
In Vivo Animal Models ◽  
Cell Spread ◽  
Draining Lymph Nodes

Human cytomegalovirus (HCMV) is a &beta;-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner&rsquo;s hypothesis where virus replicates at the site of infection, followed by replication in the draining lymph nodes, and eventually replicating within blood filtering organs. Although CMVs somewhat follow Fenner&rsquo;s hypothesis, they deviate from it by spreading primarily through innate immune cells as opposed to cell free virus. Also, in vivo CMVs infect new cells via cell to cell spread and disseminate directly to secondary organs through novel mechanisms. We review the historic and recent literature pointing to CMV&rsquo;s direct dissemination to secondary organs and the genes that it has evolved for increasing its ability to disseminate. We also highlight aspects of CMV infection for studying viral dissemination when using in vivo animal models.

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