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Article ; Online: Trained immunity: General and emerging concepts.

Vuscan, Patricia / Kischkel, Brenda / Joosten, Leo A B / Netea, Mihai G

2024

Abstract: Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non-specific protection against pathogens, innate immune cells can acquire ... ...

Abstract	Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non-specific protection against pathogens, innate immune cells can acquire antigen-agnostic memory, exhibiting increased responsiveness to secondary stimulation. This long-term de-facto innate immune memory, also termed trained immunity, is mediated through extensive metabolic rewiring and epigenetic modifications. While the upregulation of trained immunity proves advantageous in countering immune paralysis, its overactivation contributes to the pathogenesis of autoinflammatory and autoimmune disorders. In this review, we present the latest advancements in the field of innate immune memory followed by a description of the fundamental mechanisms underpinning trained immunity generation and different cell types that mediate it. Furthermore, we explore its implications for various diseases and examine current limitations and its potential therapeutic targeting in immune-related disorders.
Language	English
Publishing date	2024-03-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13326
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Article ; Online: Enduring echoes: Post-infectious long-term changes in innate immunity.

Dulfer, Elisabeth A / Joosten, Leo A B / Netea, Mihai G

European journal of internal medicine

2023

Abstract: Upon encountering pathogens, the immune system typically responds by initiating an acute and self-limiting reaction, with symptoms subsiding after the pathogen has been cleared. However, long-term post-infectious clinical symptoms can manifest months or ... ...

Abstract	Upon encountering pathogens, the immune system typically responds by initiating an acute and self-limiting reaction, with symptoms subsiding after the pathogen has been cleared. However, long-term post-infectious clinical symptoms can manifest months or even years after the initial infection. 'Trained immunity', the functional reprogramming of innate immune cells through epigenetic and metabolic rewiring, has been proposed as a key concept for understanding these long-term effects. Although trained immunity can result in enhanced protection against reinfection with heterologous pathogens, it can also contribute to detrimental outcomes. Persisting and excessive inflammation can cause tissue damage and aggravate immune-mediated conditions and cardiovascular complications. On the other hand, suppression of immune cell effector functions by long-lasting epigenetic changes can result in post-infectious immune paralysis. Distinct stimuli can evoke different trained immunity programs, potentially resulting in different consequences for the host. In this review, we provide an overview of both the adaptive and maladaptive consequences of infectious diseases. We discuss how long-term immune dysregulation in patients can be addressed by tailoring host-directed interventions and identify areas of scientific and therapeutic potential to advance further.
Language	English
Publishing date	2023-12-21
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1038679-8
ISSN	1879-0828 ; 0953-6205
ISSN (online)	1879-0828
ISSN	0953-6205
DOI	10.1016/j.ejim.2023.12.020
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Article ; Online: Beyond adaptive immunity

Mihai G. Netea / Leo A.B. Joosten

The Journal of Clinical Investigation, Vol 133, Iss

induction of trained immunity by COVID-19 adenoviral vaccines

2023 Volume 2

Abstract: ... in the fight against the pandemic. While ChAdOx1 nCoV-19 has been shown to induce adaptive B and T cell ...

Abstract	The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has resulted in much human suffering and societal disruption. The ChAdOx1 nCoV-19 vaccine against COVID-19 has had a crucial role in the fight against the pandemic. While ChAdOx1 nCoV-19 has been shown to induce adaptive B and T cell responses, which protect against COVID-19, in this issue of the JCI, Murphy et al. show that this vaccine also induces trained innate immunity. This finding contributes to a better understanding of the complex immunological effects of adenoviral-based vaccines, provides the possibility of clinically relevant heterologous effects of these vaccines, and suggests that other adenoviral-based vaccines may induce trained immunity.
Keywords	Medicine ; R
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
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Article ; Online: CHIP and gout: trained immunity?

Merriman, Tony R / Joosten, Leo A B

Blood

2022 Volume 140, Issue 10, Page(s) 1054–1056

MeSH term(s)	Clonal Hematopoiesis ; DNA-Binding Proteins ; Dioxygenases ; Gout/immunology ; Humans ; Immunity, Innate
Chemical Substances	DNA-Binding Proteins ; Dioxygenases (EC 1.13.11.-) ; TET2 protein, human (EC 1.13.11.-)
Language	English
Publishing date	2022-09-08
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022017212
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Article ; Online: Human interleukin-36γ plays a crucial role in cytokine induction during Sporothrix brasiliensis and S. schenckii infection in keratinocytes and PBMCs.

Kischkel, Brenda / Dos Santos, Jéssica C / Lopes-Bezerra, Leila / Taborda, Carlos P / Joosten, Leo A B

Microbial pathogenesis

2024 Volume 188, Page(s) 106550

Abstract: Cytokines of the interleukin (IL)-1 superfamily including the different IL-36 isoforms, have been reported as mediators of acute and chronic inflammation in human skin diseases, such as psoriasis. Here, we demonstrated for the first time that Sporothrix ... ...

Abstract	Cytokines of the interleukin (IL)-1 superfamily including the different IL-36 isoforms, have been reported as mediators of acute and chronic inflammation in human skin diseases, such as psoriasis. Here, we demonstrated for the first time that Sporothrix schenckii and S. brasiliensis, the fungi that cause subcutaneous infection sporotrichosis, can induce the expression of IL-36α, IL-36γ and IL-36Ra in human keratinocytes and primary peripheral blood mononuclear cells (PBMCs). Specifically, IL-36γ was differentially expressed by keratinocytes stimulated with Sporothrix yeasts when compared to the commensal microorganism Staphylococcus epidermidis. The exposure of keratinocytes to 24 h or 7-days culture supernatant of PBMCs stimulated with Sporothrix induced higher IL-36γ production compared to direct stimulation of keratinocytes with the live fungus. We identified that IL-36γ mRNA expression in keratinocytes is increased in the presence of IL-17, TNF, IL-1β and IL-1α and these cytokines may act synergistically to maintain IL-36γ production. Lastly, using a cohort of 164 healthy individuals, we showed that individuals carrying variants of the IL36G gene (rs11690399 and rs11683399) exhibit increased IL-36γ production as well as increased innate cytokine production after Sporothrix exposure. Importantly, stimulation of PBMCs with recombinant IL-36γ increased the production of IL-1β and IL-6, while IL-36Ra were able to decrease the concentration of these cytokines. Our findings contribute to the understanding of the pathogenesis of sporotrichosis and suggest that IL-36γ may be involved in maintaining the cytokine loop that leads to tissue destruction by exacerbating the immune response in sporotrichosis. Of high interest, we present the IL-36 signalling pathway as a potential new therapeutic target.
MeSH term(s)	Humans ; Cytokines/metabolism ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Interleukins/genetics ; Interleukins/metabolism ; Keratinocytes ; Leukocytes, Mononuclear ; Sporothrix/genetics ; Sporotrichosis
Chemical Substances	Cytokines ; Interleukin-1beta ; Interleukins ; IL36G protein, human
Language	English
Publishing date	2024-01-21
Publishing country	England
Document type	Journal Article
ZDB-ID	632772-2
ISSN	1096-1208 ; 0882-4010
ISSN (online)	1096-1208
ISSN	0882-4010
DOI	10.1016/j.micpath.2024.106550
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Article ; Online: Skin innate immune response against fungal infections and the potential role of trained immunity.

Bombassaro, Amanda / Figueiredo, Julia Marcondes / Taborda, Carlos P / Joosten, Leo A B / Vicente, Vania A / Queiroz-Telles, Flavio / Meis, Jacques F / Kischkel, Brenda

Mycoses

2024 Volume 67, Issue 1

Abstract: Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of ... ...

Abstract	Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of treatment alternatives. The first studies of trained immunity (TI) described the ability of monocytes, macrophages and natural killer (NK) cells to develop a memory-like response. However, the duration of TI does not reflect the shorter lifespan of these cells. These conclusions supported later studies showing that TI can be observed in stem and haematopoietic cells and, more recently, also in non-immune skin cells such as fibroblasts, highlighting the importance of resident cells in response to skin disorders. Besides, the participation of less studied proinflammatory cytokines in the skin immune response, such as IL-36γ, shed light into a new possibility of inflammatory pathway blockade by drugs. In this review, we will discuss the skin immune response associated with fungal infections, the role of TI in skin and clinical evidence supporting opportunities and challenges of TI and other inflammatory responses in the pathogenesis of fungal skin infections.
MeSH term(s)	Humans ; Trained Immunity ; Immunity, Innate ; Macrophages ; Monocytes ; Mycoses
Language	English
Publishing date	2024-01-28
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	392487-7
ISSN	1439-0507 ; 0933-7407
ISSN (online)	1439-0507
ISSN	0933-7407
DOI	10.1111/myc.13682
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Book ; Thesis: Targeting of cytokines in experimental arthritis

Joosten, Leonardus Antonius Bernardus

1999

Author's details	door Leonardus Antonius Bernardus Joosten
Language	English
Size	215 S. : Ill., graph. Darst.
Publishing country	Netherlands
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Nijmegen, Kath. Univ., Diss., 1999
Note	Zsfassung in niederländ. Sprache
HBZ-ID	HT012774624
ISBN	90-901-3079-9 ; 978-90-901-3079-8
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Soluble urate-induced effects on cytokine production in vitro - Assessment of methodologies and cell types.

Liu, Ruiqi / Klück, Viola / Kischkel, Brenda / Tercan, Helin / Netea, Mihai G / Crişan, Tania O / Joosten, Leo A B

Cytokine

2024 Volume 175, Page(s) 156502

Abstract: Background: Hyperuricemia has been shown to be an inducer of pro-inflammatory mediators by human primary monocytes. To study the deleterious effects of hyperuricemia, a reliable and stable in vitro model using soluble urate is needed. One recent report ... ...

Abstract	Background: Hyperuricemia has been shown to be an inducer of pro-inflammatory mediators by human primary monocytes. To study the deleterious effects of hyperuricemia, a reliable and stable in vitro model using soluble urate is needed. One recent report showed different urate-dissolving methods resulted in either pro-inflammatory or anti-inflammatory properties. The aim of this study was to compare the effect of two methods of dissolving urate on both primary human peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The two methods tested were 'pre-warming' and 'dissolving with NaOH'. Methods: Primary human PBMCs and THP-1 cells were exposed to urate solutions, prepared using the two methodologies: pre-warming and dissolving with NaOH. Afterwards, cells were stimulated with various stimuli, followed by the measurement of the inflammatory mediators IL-1β, IL-6, IL-1Ra, TNF, IL-8, and MCP-1. Results: In PBMCs, we observed an overall pro-inflammatory effect of urate, both in the pre-warming and the NaOH dissolving method. A similar pro-inflammatory effect was seen in THP-1 cells for both dissolving methods after restimulation. However, THP-1 cells exhibited pro-inflammatory profile with exposure to urate alone without restimulation. We did not find MSU crystals in our cellular assays. Conclusions: Overall, the urate dissolving methods do not have critical impact on its inflammatory properties. Soluble urate prepared using either of the two methods showed mostly pro-inflammatory effects on human primary PBMCs and monocytic cell line THP-1. However, human primary PBMCs and the THP-1 differ in their response to soluble urate without restimulation.
MeSH term(s)	Humans ; Uric Acid/pharmacology ; Uric Acid/metabolism ; Hyperuricemia/metabolism ; Leukocytes, Mononuclear/metabolism ; Sodium Hydroxide/metabolism ; Sodium Hydroxide/pharmacology ; Monocytes ; Inflammation Mediators/metabolism
Chemical Substances	Uric Acid (268B43MJ25) ; Sodium Hydroxide (55X04QC32I) ; Inflammation Mediators
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2024.156502
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Article ; Online: The future clinical implications of trained immunity.

Nica, Valentin / Popp, Radu A / Crișan, Tania O / Joosten, Leo A B

Expert review of clinical immunology

2022 Volume 18, Issue 11, Page(s) 1125–1134

Abstract: Introduction: Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands, or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, ... ...

Abstract	Introduction: Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands, or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, macrophages, and neutrophils develop an enhanced capacity to mount innate immune responses to subsequent stimuli and this is persistent due to alterations at the myeloid progenitor compartment. Areas covered: The purpose of this article is to review the current understanding of the TI process and to discuss its potential clinical implications in the near future. We address the evidence of TI involvement in various diseases, the currently developed new therapy, and discuss how TI may lead to new clinical tools to improve existing standards of care. Expert opinion: The state of the art in this domain has made considerable progress, linking TI-related mechanisms in multiple immune-mediated pathologies, starting with infections to autoimmune disorders and cancers. As a relatively new area of immunology, it has seen fast progress with many of its applications ready to be investigated in clinical settings.
MeSH term(s)	Humans ; Ligands ; Immunity, Innate ; Monocytes ; Neoplasms ; Autoimmune Diseases/therapy ; Immunologic Memory
Chemical Substances	Ligands
Language	English
Publishing date	2022-09-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2274260-8
ISSN	1744-8409 ; 1744-666X
ISSN (online)	1744-8409
ISSN	1744-666X
DOI	10.1080/1744666X.2022.2120470
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Article ; Online: Sex-biased genetic regulation of inflammatory proteins in the Dutch population.

Boahen, Collins K / Abee, Hannah / Ponce, Isis Ricaño / Joosten, Leo A B / Netea, Mihai G / Kumar, Vinod

BMC genomics

2024 Volume 25, Issue 1, Page(s) 154

Abstract: Background: Significant differences in immune responses, prevalence or susceptibility of diseases and treatment responses have been described between males and females. Despite this, sex-differentiation analysis of the genetic architecture of ... ...

Abstract	Background: Significant differences in immune responses, prevalence or susceptibility of diseases and treatment responses have been described between males and females. Despite this, sex-differentiation analysis of the genetic architecture of inflammatory proteins is largely unexplored. We performed sex-stratified meta-analysis after protein quantitative trait loci (pQTL) mapping using inflammatory biomarkers profiled using targeted proteomics (Olink inflammatory panel) of two population-based cohorts of Europeans. Results: Even though, around 67% of the pQTLs demonstrated shared effect between sexes, colocalization analysis identified two loci in the males (LINC01135 and ITGAV) and three loci (CNOT10, SRD5A2, and LILRB5) in the females with evidence of sex-dependent modulation by pQTL variants. Furthermore, we identified pathways with relevant functions in the sex-biased pQTL variants. We also showed through cross-validation that the sex-specific pQTLs are linked with sex-specific phenotypic traits. Conclusion: Our study demonstrates the relevance of genetic sex-stratified analysis in the context of genetic dissection of protein abundances among individuals and reveals that, sex-specific pQTLs might mediate sex-linked phenotypes. Identification of sex-specific pQTLs associated with sex-biased diseases can help realize the promise of individualized treatment.
MeSH term(s)	Male ; Female ; Humans ; Proteins/genetics ; Phenotype ; Quantitative Trait Loci ; Biomarkers ; Gene Expression Regulation ; Genome-Wide Association Study ; Membrane Proteins/genetics ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics ; Receptors, Immunologic/genetics ; Antigens, CD
Chemical Substances	Proteins ; Biomarkers ; SRD5A2 protein, human (EC 1.3.99.5) ; Membrane Proteins ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase (EC 1.3.99.5) ; LILRB5 protein, human ; Receptors, Immunologic ; Antigens, CD
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-024-10065-z
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