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Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways.Asymptomatic hyperuricaemia precedes and potentially contributes to the development of gout and other chronic diseases. This review summarizes what is known about the effects of uric acid on pro-inflammatory responses.

Immunotherapy is revolutionizing the treatment of diseases in which dysregulated immune responses have an important role. However, most of the immunotherapy strategies currently being developed engage the adaptive immune system. In the past decade, both myeloid (monocytes, macrophages and dendritic cells) and lymphoid (natural killer cells and innate lymphoid cells) cell populations of the innate immune system have been shown to display long-term changes in their functional programme through metabolic and epigenetic programming. Such reprogramming causes these cells to be either hyperresponsive or hyporesponsive, resulting in a changed immune response to secondary stimuli. This de facto innate immune memory, which has been termed ‘trained immunity’, provides a powerful ‘targeting framework’ to regulate the delicate balance of immune homeostasis, priming, training and tolerance. In this Opinion article, we set out our vision of how to target innate immune cells and regulate trained immunity to achieve long-term therapeutic benefits in a range of immune-related diseases. These include conditions characterized by excessive trained immunity, such as inflammatory and autoimmune disorders, allergies and cardiovascular disease and conditions driven by defective trained immunity, such as cancer and certain infections.Cells in the innate immune system can display adaptive characteristics that lead to increased responsiveness to secondary stimulation by pathogens. This innate immune memory has been termed ‘trained immunity’. Here, Mulder and colleagues describe the mechanisms responsible for the induction of trained immunity and propose strategies to regulate it as a potential treatment of immune-related diseases.

Intravesical BCG instillation is the gold-standard adjuvant immunotherapy for patients with high-risk non-muscle-invasive bladder cancer. However, the precise mechanism of action by which BCG asserts its beneficial effects is still unclear. BCG has been shown to induce a non-specific enhancement of the biological function in cells of the innate immune system, creating a de facto heterologous immunological memory that has been termed trained immunity. Trained immunity or innate immune memory enables innate immune cells to mount a more robust response to secondary non-related stimuli after being initially primed (or trained) by a challenge such as BCG. BCG-induced trained immunity is characterized by the metabolic rewiring of monocyte intracellular metabolism and epigenetic modifications, which subsequently lead to functional reprogramming effects, such as an increased production of cytokines, on restimulation. Results from BCG vaccination studies in humans show that trained immunity might at least partly account for the heterologous beneficial effects of BCG vaccination. Additionally, immunity might have a role in the effect of BCG immunotherapy for bladder cancer. Based on these indications, we propose that trained immunity could be one of the important mechanisms mediating BCG immunotherapy and could provide a basis for further improvements towards a personalized approach to BCG therapy in non-muscle-invasive bladder cancer.The precise mechanism of action by which BCG acts in bladder cancer therapy is unclear. BCG induces a non-specific enhancement of the biological function of innate immune cells, creating an immunological memory known as trained immunity. In this Perspective, the authors propose that trained immunity could be an important mechanism mediating BCG immunotherapy and could contribute to a personalized approach to BCG therapy in patients with bladder cancer.

Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections. Transgenerational transmission of acquired immunological traits has been demonstrated in invertebrates and plants but not mammals. Katzmarski et al. demonstrate that trained immunity that protects against heterologous infections can be transmitted to F2 offspring.

The fourth Innate Immune Memory meeting was held in the historic city of Nijmegen, in the eastern-central part of the Netherlands, to discuss the basic and translational aspects of innate immune memory, popularly known as ‘trained immunity’.

Adaptive features of innate immunity, recently described as “trained immunity,” have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte–independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.

Interleukin-1β (IL-1β)–mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8⁺ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti–PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti–PD-1 therapy.

Background Activation of the NLRP3 inflammasome in gout amplifies the inflammatory response and mediates further damage. In the current study, we assessed the therapeutic effect of OLT1177, an orally active NLRP3 inflammasome inhibitor that is safe in humans, in murine acute arthritis models. Methods Zymosan or monosodium urate (MSU) crystals were injected intra-articularly (i.a.) into mouse knee joints to induce reactive or gouty arthritis. Joint swelling, articular cell infiltration, and synovial cytokines were evaluated 25 hours and 4 hours following zymosan or MSU challenge, respectively. OLT1177 was administrated intraperitoneally by oral gavage or in the food by an OLT1177-enriched diet. Results OLT1177 reduced zymosan-induced joint swelling ( p  < 0.001), cell influx ( p  < 0.01), and synovial levels of interleukin (IL)-1β, IL-6, and chemokine (C-X-C motif) ligand 1 (CXCL1) ( p  < 0.05), respectively, when compared with vehicle-treated mice. Plasma OLT1177 levels correlated ( p  < 0.001) dose-dependently with reduction in joint inflammation. Treatment of mice with OLT1177 limited MSU crystal articular inflammation ( p  > 0.0001), which was associated with decreased synovial IL-1β, IL-6, myeloperoxidase, and CXCL1 levels ( p  < 0.01) compared with vehicle-treated mice. When administrated orally 1 hour after MSU challenge, OLT1177 reduced joint inflammation, processing of IL-1β, and synovial phosphorylated c-Jun N-terminal kinase compared with the vehicle group. Mice were fed an OLT1177-enriched diet for 3 weeks and then challenged i.a. with MSU crystals. Joint swelling, synovial IL-1β, and expression of Nlrp3 and Il1b were significantly reduced in synovial tissues in mice fed an OLT1177-enriched diet when compared with the standard diet group. Conclusions Oral OLT1177 is highly effective in ameliorating reactive as well as gouty arthritis.

Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow progenitors [M. Divangahi et al., Nat. Immunol. 22, 2–6 (2021)]. Innate immune cells, however, do not exclusively differentiate between foreign and self but also react to host-derived molecules referred to as alarmins. Extracellular “labile” heme, released during infections, is a bona fide alarmin promoting myeloid cell activation [M. P. Soares, M. T. Bozza, Curr. Opin. Immunol. 38, 94–100 (2016)]. Here, we report that labile heme is a previously unrecognized inducer of trained immunity that confers long-term regulation of lineage specification of hematopoietic stem cells and progenitor cells. In contrast to previous reports on trained immunity, essentially mediated by pathogen-associated molecular patterns, heme training depends on spleen tyrosine kinase signal transduction pathway acting upstream of c-Jun N-terminal kinases. Heme training promotes resistance to sepsis, is associated with the expansion of self-renewing hematopoetic stem cells primed toward myelopoiesis and to the occurrence of a specific myeloid cell population. This is potentially evoked by sustained activity of Nfix, Runx1, and Nfe2l2 and dissociation of the transcriptional repressor Bach2. Previously reported trained immunity inducers are, however, infrequently present in the host, whereas heme abundantly occurs during noninfectious and infectious disease. This difference might explain the vanishing protection exerted by heme training in sepsis over time with sustained long-term myeloid adaptations. Hence, we propose that trained immunity is an integral component of innate immunity with distinct functional differences on infectious disease outcome depending on its induction by pathogenic or endogenous molecules.

The human gut microbiota is increasingly recognized as an important factor in modulating innate and adaptive immunity through release of ligands and metabolites that translocate into circulation. Urbanizing African populations harbor large intestinal diversity due to a range of lifestyles, providing the necessary variation to gauge immunomodulatory factors. Here, we uncover a gradient of intestinal microbial compositions from rural through urban Tanzanian, towards European samples, manifested both in relative abundance and genomic variation observed in stool metagenomics. The rural population shows increased Bacteroidetes , led by Prevotella copri , but also presence of fungi. Measured ex vivo cytokine responses were significantly associated with 34 immunomodulatory microbes, which have a larger impact on circulating metabolites than non-significant microbes. Pathway effects on cytokines, notably TNF-α and IFN-γ, differential metabolome analysis and enzyme copy number enrichment converge on histidine and arginine metabolism as potential immunomodulatory pathways mediated by Bifidobacterium longum and Akkermansia muciniphila . The authors profile stool metagenomics and plasma metabolomics in Tanzanian individuals and uncover a gradient of gut microbial profiles, from rural through urban Tanzania towards Western populations. Integration with ex vivo blood microbial stimulations reveals immune responses associated with histidine and arginine pathways, mediated by Bifidobacterium longum and Akkermansia muciniphila .