Tatiane S. Lima

California State Polytechnic University

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Melissa B. Lodoen

University of California, Irvine

Sandra Coccuzzo Sampaio

Instituto Butantan

Arne Rietsch

Case Western Reserve University

Michaela Marshall

University of California, Irvine

Martin Minns

University of California, Irvine

Serena Abbondante

University of California, Irvine

George Dubyak

Case Western Reserve University

Maria Cristina Cirillo

Instituto Butantan

Lanny Gov

University of California, Irvine

Karl Liboro

University of California, Irvine

Cooperative Institutions

University of California, Irvine

Instituto Butantan

Clinics Hospital of Ribeirão Preto

Universidade de São Paulo

University of California System

Case Western Reserve University

Irvine University

Boston Children's Hospital

Stanford University

National Institutes of Health

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The NLRP3 inflammasome selectively drives IL-1β secretion byPseudomonas aeruginosainfected neutrophils and regulates bacterial killingin vivo

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Martin Minns Karl Liboro Tatiane S. Lima Serena Abbondante Brandon A. Miller

ABSTRACT Macrophages infected with Gram-negative bacteria expressing Type III secretion system (T3SS) activate the NLRC4 inflammasome, resulting in Gasdermin D (GSDMD)-mediated IL-1β secretion and pyroptosis. Here we examined inflammasome signaling in neutrophils infected with Pseudomonas aeruginosa strain PAO1 that expresses the T3SS effectors ExoS and ExoT. IL-1β secretion by neutrophils required the T3SS needle and translocon proteins and GSDMD. In macrophages, PAO1 and mutants lacking ExoS and ExoT ( ΔexoST ) stimulated NLRC4 for IL-1β secretion. While IL-1β release from ΔexoST infected neutrophils was also NLRC4-dependent, this was redirected to NLRP3-dependence by PAO1 infection via the ADP ribosyl transferase activity of ExoS. Genetic and pharmacologic approaches revealed that NLRP3, but not NLRC4, was essential for bacterial killing and limiting disease severity in a murine model of P. aeruginosa corneal infection. This reveals a novel role for ExoS ADPRT in regulating inflammasome subtype usage by neutrophils versus macrophages and an unexpected role for NLRP3 in P. aeruginosa keratitis.

NLRC4

Pyroptosis

10.1101/2022.04.07.487503

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Crotoxin-Treated Macrophages Stimulate ROS Production and Killing Activity in Co-Cultured Neutrophils

Renata Begliomini Bruno De-Oliveira Ellen Emi Kato Tatiane S. Lima Tatiana Carolina Alba‐Loureiro Rui Curi

Crotoxin (CTX), the predominant toxin in Crotalus durissus terrificus snake venom (CdtV), has anti-inflammatory and immunomodulatory effects. Despite its inhibitory action on neutrophil migration and phagocytosis, CTX does not directly affect the production of reactive oxygen species (ROS) by the neutrophils. In contrast, it enhances the generation of reactive oxygen and nitrogen intermediates by macrophages. Given the importance of macrophage-neutrophil interactions in innate antimicrobial defense, the aim of this study was to investigate the effect of CTX on neutrophil ROS production and killing activity, either through CTX-treated macrophage co-culture or conditioned medium of CTX-treated macrophages. The results showed an important modulatory action of CTX on the neutrophil function as well as neutrophil-macrophage interactions, as demonstrated by the increased production of hydrogen peroxide, hypochlorous acid, nitric oxide and TNF-α, along with the increased fungicidal activity of neutrophils.

Hypochlorous acid

Reactive nitrogen species

10.20944/preprints201805.0322.v1

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Beyond an inflammatory mediator: Interleukin‐1 in neurophysiology

Experimental Physiology (2023)

Tatiane S. Lima

Abstract Since its discovery in the early 1940s, the interleukin‐1 (IL‐1) cytokine family has been associated primarily with acute and chronic inflammation. The family member IL‐1β is produced by different leucocytes, endothelial cells and epithelial cells. This cytokine has been characterized as a key modulator of inflammation and innate immunity because it induces the transcription of several downstream inflammatory genes. More recently, several groups have demonstrated that IL‐1β production is also required to maintain homeostasis in several organ systems. This review focuses on providing an overview of the more recently characterized role of IL‐1β in the physiology of the CNS. So far, IL‐1β signalling has been implicated in neuronal survival, neurite growth, synaptic pruning, synaptic transmission, neuroplasticity and neuroendocrine functions.

Mediator

Homeostasis

10.1113/ep090780

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Caracterização das ações do veneno de Crotalus durissus terrificus sobre funções de neutrófilos

Tatiane S. Lima

10.11606/d.41.2010.tde-21022011-132634

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Neutrophil IL-1β secretion induced by ExoS expressing Pseudomonas aeruginosa is dependent on NLRP3 and Gasdermin D

Research Square (Research Square) (2022)

Martin Minns Tatiane S. Lima Karl Liboro Serena Abbondante Michaela Marshall

Abstract Macrophages infected with Gram-negative bacteria expressing flagellin or Type III secretion system (T3SS) structural proteins are known to activate the NLRC4 inflammasome, resulting in caspase-1 and Gasdermin D (GSDMD) cleavage, IL-1β secretion and pyroptotic cell death. We examined the role of these mediators in IL-1β secretion by neutrophils infected with Pseudomonas aeruginosa strain PAO1 that expresses the Type III secretion system (T3SS) effectors ExoS and ExoT. We found that IL-1β secretion by neutrophils was dependent on expression of the T3SS needle and translocon proteins. Although pro-GSDMD and pro-GSDME were processed in PAO1 infected neutrophils, only GSDMD was required for IL-1β secretion. PAO1 – induced IL-1β secretion by macrophages was NLRC4 dependent, IL-1β secretion by neutrophils utilized NLRC4 only in the absence of P. aeruginosa exoenzymes. Instead, PAO1 – induced IL-1β secretion required NLRP3, which mediated by ExoS ADP ribosyl transferase activity. Overall, these findings reveal fundamental differences between neutrophils and macrophages in IL-1β secretion in response to pathogenic bacteria.

NLRC4

Pyroptosis

Flagellin

10.21203/rs.3.rs-1533552/v1

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NLRP3 and Potassium Efflux Drive Rapid IL-1β Release from Primary Human Monocytes during Toxoplasma gondii Infection

The Journal of Immunology (2017)

Lanny Gov Christine A. Schneider Tatiane S. Lima William Pandori Melissa B. Lodoen

IL-1β is produced by myeloid cells and acts as a critical mediator of host defense during infection and injury. We found that the intracellular protozoan parasite Toxoplasma gondii induced an early IL-1β response (within 4 h) in primary human peripheral blood monocytes isolated from healthy donors. This process involved upregulation of IL-1β, IL-1RN (IL-1R antagonist), and NLRP3 transcripts, de novo protein synthesis, and the release of pro- and mature IL-1β from infected primary monocytes. The released pro-IL-1β was cleavable to mature bioactive IL-1β in the extracellular space by the protease caspase-1. Treatment of primary monocytes with the NLRP3 inhibitor MCC950 or with extracellular potassium significantly reduced IL-1β cleavage and release in response to T. gondii infection, without affecting the release of TNF-α, and indicated a role for the inflammasome sensor NLRP3 and for potassium efflux in T. gondii-induced IL-1β production. Interestingly, T. gondii infection did not induce an IL-1β response in primary human macrophages derived from the same blood donors as the monocytes. Consistent with this finding, NLRP3 was downregulated during the differentiation of monocytes to macrophages and was not induced in macrophages during T. gondii infection. To our knowledge, these findings are the first to identify NLRP3 as an inflammasome sensor for T. gondii in primary human peripheral blood cells and to define an upstream regulator of its activation through the release of intracellular potassium.

Efflux

10.4049/jimmunol.1700245

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HYPERACUTE REJECTION WITH NEGATIVE CYTOTOXICITY CROSSMATCH AND HLA BASED ALLOCATION PROGRAM- IS IT FEASIBLE TO PERFORM T CELL FLOW CYTOMETRY CROSSMATCH (FCXM) FOR ALL?

Transplantation (2010)

Luciana Tanajura Santamaria Saber M. A. Giavanetti Tatiane S. Lima Luciane Mota Lima Cyntia Silveira

Saber, L. T.S.; Giavanetti, M. A.; Lima, T. S.; Lima, L. M.; Silveira, C.; Garcia, T. M.P.; Lucera, A. P.; Donadi, E. A. Author Information

10.1097/00007890-201007272-01006

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Mechanisms of Human Innate Immune Evasion by Toxoplasma gondii

Frontiers in Cellular and Infection Microbiology (2019)

Tatiane S. Lima Melissa B. Lodoen

Toxoplasma gondii is an intracellular protozoan parasite of global importance that can remarkably infect, survive, and replicate in nearly all mammalian cells. Notably, 110 years after its discovery, Toxoplasmosis is still a neglected parasitic infection. Although most human infections with T. gondii are mild or asymptomatic, T. gondii infection can result in life-threatening disease in immunocompromised individuals and in the developing fetus due to congenital infection, underscoring the role of the host immune system in controlling the parasite. Recent evidence indicates that T. gondii elicits a robust innate immune response during infection. Interestingly, however, T. gondii has evolved strategies to successfully bypass or manipulate the immune system and establish a life-long infection in infected hosts. In particular, T. gondii manipulates host immunity through the control of host gene transcription and dysregulation of signaling pathways that result in modulation of cell adhesion and migration, secretion of immunoregulatory cytokines, production of microbicidal molecules, and apoptosis. Many of these host-pathogen interactions are governed by parasite effector proteins secreted from the apical secretory organelles, including the rhoptries and dense granules. Here, we review recent findings on mechanisms by which T. gondii evades host innate immunity, with a focus on parasite evasion of the human innate immune system.

Evasion (ethics)

Toxoplasmosis

10.3389/fcimb.2019.00103

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Citations (145)

Crotoxin, a rattlesnake toxin, induces a long-lasting inhibitory effect on phagocytosis by neutrophils

Experimental Biology and Medicine (2012)

Tatiane S. Lima Sálua C Cataneo Ana Caroline C Iritus Sandra Coccuzzo Sampaio Maisa S. Della-Casa

Crotalus durissus terrificus snake venom (CdtV) has long-lasting anti-inflammatory properties and inhibits the spreading and phagocytic activity of macrophages. Crotoxin (CTX), the main component of CdtV, is responsible for these effects. Considering the role of neutrophils in the inflammatory response and the lack of information about the effect of CdtV on neutrophils, the aim of this study was to investigate the effect of CdtV and CTX on two functions of neutrophils, namely phagocytosis and production of reactive oxygen species, and on the intracellular signaling involved in phagocytosis, particularly on tyrosine phosphorylation and rearrangements of the actin cytoskeleton. Our results showed that the incubation of neutrophils with CdtV or CTX, at different concentrations, or the subcutaneous injection of CdtV or CTX in rats two hours or one, four or 14 days before or one hour after the induction of inflammation inhibited the phagocytic activity of neutrophils. Furthermore, these in vitro and in vivo effects were associated with CdtV and CTX inhibition of tyrosine phosphorylation and consequently actin polymerization. Despite the inhibitory effect on phagocytosis, this study demonstrated that CdtV and CTX did not alter the production of the main reactive oxygen species. Therefore, this study characterized, for the first time, the actions of CdtV on neutrophils and demonstrated that CTX induces a long-lasting inhibition of tyrosine phosphorylation and consequently phagocytosis. We suggest that CTX represents a potential natural product in controlling inflammatory diseases, since a single dose exerts a long-lasting effect on intracellular signaling involved in phagocytosis by neutrophils.

10.1258/ebm.2012.012010

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Citations (22)

Toxoplasma gondii activates a Syk-CARD9-NF-κB signaling axis and gasdermin D-independent release of IL-1β during infection of primary human monocytes

PLoS Pathogens (2019)

William Pandori Tatiane S. Lima Sharmila Mallya Tiffany H. Kao Lanny Gov

IL-1β is a potent pro-inflammatory cytokine that promotes immunity and host defense, and its dysregulation is associated with immune pathology. Toxoplasma gondii infection of myeloid cells triggers the production and release of IL-1β; however, the mechanisms regulating this pathway, particularly in human immune cells, are incompletely understood. We have identified a novel pathway of T. gondii induction of IL-1β via a Syk-CARD9-NF-κB signaling axis in primary human peripheral blood monocytes. Syk was rapidly phosphorylated during T. gondii infection of primary monocytes, and inhibiting Syk with the pharmacological inhibitors R406 or entospletinib, or genetic ablation of Syk in THP-1 cells, reduced IL-1β release. Inhibition of Syk in primary cells or deletion of Syk in THP-1 cells decreased parasite-induced IL-1β transcripts and the production of pro-IL-1β. Furthermore, inhibition of PKCδ, CARD9/MALT-1 and IKK reduced p65 phosphorylation and pro-IL-1β production in T. gondii-infected primary monocytes, and genetic knockout of PKCδ or CARD9 in THP-1 cells also reduced pro-IL-1β protein levels and IL-1β release during T. gondii infection, indicating that Syk functions upstream of this NF-κB-dependent signaling pathway for IL-1β transcriptional activation. IL-1β release from T. gondii-infected primary human monocytes required the NLRP3-caspase-1 inflammasome, but interestingly, was independent of gasdermin D (GSDMD) cleavage and pyroptosis. Moreover, GSDMD knockout THP-1 cells released comparable amounts of IL-1β to wild-type THP-1 cells after T. gondii infection. Taken together, our data indicate that T. gondii induces a Syk-CARD9/MALT-1-NF-κB signaling pathway and activation of the NLRP3 inflammasome for the release of IL-1β in a cell death- and GSDMD-independent manner. This research expands our understanding of the molecular basis for human innate immune regulation of inflammation and host defense during parasite infection.

THP1 cell line

10.1371/journal.ppat.1007923

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Citations (54)