Monosodium Urate Crystals Promote Innate Anti-Mycobacterial Immunity and Improve BCG Efficacy as a Vaccine against Tuberculosis

Taus, Francesco; Santucci, Marilina B.; Greco, Emanuela A.; Morandi, Matteo; Palucci, Ivana; Mariotti, Sabrina; Poerio, Noemi; Nisini, Roberto; Delogu, Giovanni; Fraziano, Maurizio

doi:10.1371/journal.pone.0127279

Cited by 15 publications

(16 citation statements)

References 37 publications

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“…It is tempting to speculate that MSU crystals could also prime circulating or resident cells for elevated inflammatory responses via innate immune memory‐like mechanisms. Indeed, one study did show that MSU crystals were able to enhance the phagocytosis and killing capacity of murine macrophages leading to a more enduring response to BCG vaccination in mice …”

Section: Urate‐induced Immune Programmingmentioning

confidence: 99%

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

Cabău

Crişan

Klück

et al. 2019

Immunological Reviews

166

110

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Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage‐associated molecules leading to an enhanced non‐specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low‐grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long‐term systemic inflammation seen in gout. We revisit existing evidence for urate‐induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.

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Section: Urate‐induced Immune Programmingmentioning

confidence: 99%

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

Cabău

Crişan

Klück

et al. 2019

Immunological Reviews

166

110

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“…Mycoacterium bovis BCG Pasteur strain (TMC1011) was grown and titred as described14. BCG transformed with the plasmid carrying luciferase gene (BCG-lux), kindly provided by Prof. R. Reljic from S. George’s University of London (UK), was grown as previously described55.…”

Section: Methodsmentioning

confidence: 99%

“…After removal of extracellular bacilli, cells were treated with the indicated different ABLs added to a ratio of 1 to 1 (ABL:cell). Intracellular BCG growth was monitored by CFU assay14 or by luminometric assay55 performed after 3 hour exposure and at day 3 post-infection, by plating bacilli in triplicate after lysis of cells with saponin. Mycobacterial luminescence has been evaluated by Varioskan LUX Multimode Microplate Reader (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…Mycobacterium tuberculosis (MTB), as well as the attenuated M. bovis Bacille Calmette-Guerin (BCG), interfere with phagolysosome maturation1415 by depleting the phagosome of PI3P. Several mycobacterial products, including lipoarabinomannan (LAM), Secretory acid phosphatase (SapM), Zinc-dependent metalloprotease (ZMP), 6 kDa early secreted antigenic target (ESAT-6) and Mycobacterium tuberculosis Protein Tyrosine Phosphatase A (MptpA), act in concert1617 to inhibit the conversion of the Mycobacterium -containing phagosome into a phagolysosome, where the bacteria would finally be degraded.…”

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confidence: 99%

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Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance

Poerio

Bugli

Taus

et al. 2017

Sci Rep

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Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.

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“…The last has been demonstrated in studies that have demonstrated that urate crystals acting as an adjuvant enhance antibody response following vaccination against hepatitis B surface antigen (5), tuberculosis (6) and tumors (7). It has been also proposed that aluminum hydroxide, the most widely adjuvant used in human vaccines, exerts its effect by activating dendritic cells through local cell injury and urate release (8).…”

Section: Introductionmentioning

confidence: 99%

Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation

et al. 2017

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Abstract. Uric acid is a known danger associated molecular pattern molecule able to induce inflammation following internalization of its crystals by cells of the innate immune system. By activating antigen-presenting cells, urate boosts adaptive immunity as well. Furthermore, urate crystals can induce proliferation of isolated T-cells, which are unable to phagocytose crystal particles. In light of the evidence that urate crystals can also activate dendritic cells and macrophages without prior internalization but through sequestration of lipid rafts (and consequently receptors clustering in a non specific manner), the authors evaluated whether such a mechanism is involved in the direct activation of T-cells by urate crystals. In the present study, isolated human T-cells were cultured with or without urate at a concentration above its crystallization level. The expression and phosphorylation state of the T-cell receptor (TCR) complex zeta chain and the expression of the master regulator of cell proliferation c-Myc were assessed by western blotting. T-cell proliferation was measured by bromodeoxyuridine assay. Collectively, the results indicated that urate increased zeta chain phosphorylation indicating that it induces activation of TCR complex directly, since zeta chain phosphorylation takes place at the cell membrane and is a very proximal event in TCR complex-mediated signal transduction. In parallel, urate increased the expression of the transcription factor c-Myc and induced T-cell proliferation. In conclusion, urate crystals directly activate the TCR complex and induce T-cell proliferation.

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Monosodium Urate Crystals Promote Innate Anti-Mycobacterial Immunity and Improve BCG Efficacy as a Vaccine against Tuberculosis

Cited by 15 publications

References 37 publications

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance

Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation

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