scholarly journals RIPK3 facilitates host and pathogen interactions after oral Toxoplasma gondii infection

2020 ◽  
Author(s):  
Patrick W. Cervantes ◽  
Laura J. Knoll
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Inflammatory Cell ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Parasite Burden ◽  
Kinase Domain ◽  
Protection Mechanism ◽  
Cell Death Pathway ◽  
Toxoplasma Gondii Infection

AbstractToxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a pro-inflammatory cell death pathway apart of the innate immune response that has evolved to control pathogenic infection. In this study we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce pro-inflammatory necroptosis cell death and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3-/-), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection even with higher parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villi immunopathology but RIPK3-/- mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed lineage kinase domain like pseudokinase null (MLKL-/-) mice. We found MLKL-/- mice to succumb to oral T. gondii infection the same as wild type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of pro-inflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

scholarly journals RIPK3 Facilitates Host Resistance to Oral Toxoplasma gondii Infection

2021 ◽  
Vol 89 (5) ◽  
Author(s):  
Patrick W. Cervantes ◽  
Bruno Martorelli Di Genova ◽  
Billy Joel Erazo Flores ◽  
Laura J. Knoll
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Parasite Burden ◽  
Kinase Domain ◽  
Content Type ◽  
Protection Mechanism ◽  
Cell Death Pathway ◽  
Toxoplasma Gondii Infection

ABSTRACT Toxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a proinflammatory cell death pathway apart from the innate immune response that has evolved to control pathogenic infection. In this study, we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce proinflammatory necroptosis cell death, and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3−/−), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection without a reduction in parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villus immunopathology, but RIPK3−/− mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed-lineage kinase domain-like pseudokinase null (MLKL−/−) mice. We found MLKL−/− mice succumbed to oral T. gondii infection the same as wild-type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of proinflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

scholarly journals A Protective and Pathogenic Role for Complement During Acute Toxoplasma gondii Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Patricia M. Sikorski ◽  
Alessandra G. Commodaro ◽  
Michael E. Grigg
Keyword(s):  
Toxoplasma Gondii ◽  
Complement System ◽  
Inflammatory Responses ◽  
Membrane Attack Complex ◽  
Parasite Burden ◽  
Immune Serum ◽  
Factor H ◽  
Complement Regulatory Proteins ◽  
Serum Killing ◽  
Toxoplasma Gondii Infection

The infection competence of the protozoan pathogen Toxoplasma gondii is critically dependent on the parasite’s ability to inactivate the host complement system. Toxoplasma actively resists complement-mediated killing in non-immune serum by recruiting host-derived complement regulatory proteins C4BP and Factor H (FH) to the parasite surface to inactivate surface-bound C3 and limit formation of the C5b-9 membrane attack complex (MAC). While decreased complement activation on the parasite surface certainly protects Toxoplasma from immediate lysis, the biological effector functions of C3 split products C3b and C3a are maintained, which includes opsonization of the parasite for phagocytosis and potent immunomodulatory effects that promote pro-inflammatory responses and alters mucosal defenses during infection, respectively. In this review, we discuss how complement regulation by Toxoplasma controls parasite burden systemically but drives exacerbated immune responses locally in the gut of genetically susceptible C57BL/6J mice. In effect, Toxoplasma has evolved to strike a balance with the complement system, by inactivating complement to protect the parasite from immediate serum killing, it generates sufficient C3 catabolites that signal through their cognate receptors to stimulate protective immunity. This regulation ultimately controls tachyzoite proliferation and promotes host survival, parasite persistence, and transmissibility to new hosts.

scholarly journals The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Diane Moujalled ◽  
Pradnya Gangatirkar ◽  
Maria Kauppi ◽  
Jason Corbin ◽  
Marion Lebois ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Kinase Domain ◽  
Cell Swelling ◽  
Platelet Production ◽  
Upstream Regulator ◽  
Cell Death Pathway ◽  
Cell Death Program ◽  
Signalling Cascade ◽  
Terminal Effector

AbstractNecroptosis is a pro-inflammatory cell death program executed by the terminal effector, mixed lineage kinase domain-like (MLKL). Previous studies suggested a role for the necroptotic machinery in platelets, where loss of MLKL or its upstream regulator, RIPK3 kinase, impacted thrombosis and haemostasis. However, it remains unknown whether necroptosis operates within megakaryocytes, the progenitors of platelets, and whether necroptotic cell death might contribute to or diminish platelet production. Here, we demonstrate that megakaryocytes possess a functional necroptosis signalling cascade. Necroptosis activation leads to phosphorylation of MLKL, loss of viability and cell swelling. Analyses at steady state and post antibody-mediated thrombocytopenia revealed that platelet production was normal in the absence of MLKL, however, platelet activation and haemostasis were impaired with prolonged tail re-bleeding times. We conclude that MLKL plays a role in regulating platelet function and haemostasis and that necroptosis signalling in megakaryocytes is dispensable for platelet production.

scholarly journals Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1823 ◽  
Author(s):  
Jenny Sprooten ◽  
Pieter De Wijngaert ◽  
Isaure Vanmeerbeek ◽  
Shaun Martin ◽  
Peter Vangheluwe ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Inflammatory Cell ◽  
Necrotic Cell Death ◽  
Immunogenic Cell Death ◽  
Necrotic Cell ◽  
Cell Death Pathway ◽  
Immune Checkpoint Blockers ◽  
Anticancer Immunity

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To “break” cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

scholarly journals Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide

2019 ◽  
Vol 116 (14) ◽  
pp. 2226-2238 ◽  
Author(s):  
Tetsuo Horimatsu ◽  
Andra L Blomkalns ◽  
Mourad Ogbi ◽  
Mary Moses ◽  
David Kim ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Cell ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Aortic Aneurysms ◽  
Cell Infiltration ◽  
Protective Effects ◽  
Abdominal Aortic ◽  
G Protein Coupled

Abstract Aims Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusion Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

scholarly journals Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

2020 ◽  
Author(s):  
Anna Negroni ◽  
Eleonora Colantoni ◽  
Salvatore Cucchiara ◽  
Laura Stronati
Keyword(s):  
Cell Death ◽  
Intestinal Epithelium ◽  
Inflammatory Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Kinase Domain ◽  
Interacting Protein ◽  
New Concepts ◽  
Independent Form ◽  
Cellular Turnover

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

scholarly journals Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis

2020 ◽  
Author(s):  
Alex Rosenberg ◽  
L. David Sibley
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Host Cell ◽  
Kinase Domain ◽  
Effector Proteins ◽  
Type I ◽  
Immune Functions ◽  
Protein Kinase R ◽  
Repressor Complex

SummaryDuring infection, Toxoplasma gondii translocates effector proteins directly into its host cell to subvert various signaling pathways. Here we characterize a novel secreted effector that localizes to the host cell nucleus where it modulates NCoR/SMRT repressor complex levels to repress interferon regulated genes involved in cell death. Type I and type II interferons upregulate many genes including protein kinase R (PKR), inducing formation of the necrosome complex that activates Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) to execute necrotic cell death. Toxoplasma NCoR/SMRT modulator (TgNSM) acts together with another secreted effector TgIST, previously shown to down-modulate IFN-γ signaling to block immune functions. Together TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis, assuring survival of intracellular cysts, and maintenance of chronic infection.

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