An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma

Kool, Mirjam; Willart, Monique; Nimwegen, Menno van; Bergen, Ingrid M.; Pouliot, Philippe; Virchow, J. Christian; Rogers, N; Osorio, Fabiola; Sousa, Caetano Reis e; Hammad, Hamida; Lambrecht, Bart

doi:10.1016/j.immuni.2011.04.012

Cited by 28 publications

(34 citation statements)

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“…Some studies have suggested that the adjuvant activity of alum is mediated by the cytosolic nucleotide-binding oligomerization domain-containing protein (Nod)-like receptor (NLR), NLRP3 (5-7). However, these findings are controversial (8)(9)(10), and there is a lack of consensus regarding the mechanisms by which alum induces systemic Th2 immunity (11,12). Although many naturally occurring allergens and allergenic extracts are used to study Th2-driven responses, these preparations often are contaminated with multiple MAMPs (13,14), thereby confounding the interpretation of the specific roles of different MAMPs in the generation of Th2 immunity in these contexts.…”

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confidence: 99%

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Magalhães¹,

Rubino

Travassos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Although a number of studies have examined the development of T-helper cell type 2 (Th2) immunity in different settings, the mechanisms underlying the initiation of this arm of adaptive immunity are not well understood. We exploited the fact that immunization with antigen plus either nucleotide-binding oligomerization domain-containing proteins 1 (Nod1) or 2 (Nod2) agonists drives Th2 induction to understand how these pattern-recognition receptors mediate the development of systemic Th2 immune responses. Here, we show in bone-marrow chimeric mice that Nod1 and Nod2 expression within the stromal compartment is necessary for priming of effector CD4 + Th2 responses and specific IgG1 antibodies. In contrast, sensing of these ligands by dendritic cells was not sufficient to induce Th2 immunity, although these cells contribute to the response. Moreover, we determined that CD11c + cells were the critical antigen-presenting cells, whereas basophils and B cells did not affect the capacity of Nod ligands to induce CD4 + Th2 effector function. Finally, we found that full Th2 induction upon Nod1 and Nod2 activation was dependent on both thymic stromal lymphopoietin production by the stromal cells and the up-regulation of the costimulatory molecule, OX40 ligand, on dendritic cells. This study provides in vivo evidence of how systemic Th2 immunity is induced in the context of Nod stimulation. Such understanding will influence the rational design of therapeutics that could reprogram the immune system during an active Th1–mediated disease, such as Crohn's disease.

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confidence: 99%

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Magalhães¹,

Rubino

Travassos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…DCs take up inhaled HDM allergen and transport it to the draining mediastinal lymph nodes (MLNs), where they polarize the Th cell immune response, helped by basophils, innate lymphoid cells type 2 (ILC2s), and B cells (Coquet et al, 2015;Hammad et al, 2010;Oliphant et al, 2014;Plantinga et al, 2013). Activation of DCs occurs through the release of epithelial cytokines like thymic stromal lymphopoietin (TSLP), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-25, and the IL-1 family members IL-1a and IL-33 (Hammad et al, 2009;Kool et al, 2011;Phipps et al, 2009;Willart et al, 2012). Some of these lung-tissue-derived cytokines like IL-33 also induce cytokine production by ILC2s and tissue-resident memory Th2 cells (Coquet et al, 2015;Endo et al, 2015;Guo et al, 2015;Klein Wolterink et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

et al. 2016

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“…Alum crystals can activate the nucleotide binding oligomerization domain-like receptor protein 3 inflammasome leading to the release of mature bioactive IL-1b and IL-18, whose effects could combine with those of IL-36b. At the site of injection, Alum causes tissue damage and cell death that indirectly stimulate nucleotide binding oligomerization domainlike receptor protein 3 via the release of danger-associated molecular patterns such as uric acid, DNA, and alarmins (45,46). These local effects of Alum did not lead to any detectable circulating cytokine levels in AD or NN mice.…”

Section: Discussionmentioning

confidence: 97%

IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

Palomo

Mastelic-Gavillet

Woldt

et al. 2016

The Journal of Immunology

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Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36β to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36β with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates. This neonatal toxicity was associated with high Il36r mRNA expression in neonatal liver, resulting in increased cytokine production. Liver Il36r mRNA expression decreased with the termination of fetal liver hematopoiesis, and this decrease correlated with a complete protection from TT/Alum/IL-36β–induced mortality. The combination of IL-36β and TT/Alum induced the rapid production of TNF-α and IFN-γ by liver myeloid and lymphoid cells, respectively. These responses were less marked when IL-36β was used alone, with no adverse effect. The toxicity of IL-36β + TT/Alum was abrogated by the administration of a neutralizing anti–TNF-α Ab, confirming causality. In conclusion, liver myeloid cells in neonatal mice are an important source of proinflammatory cytokines that may lead to TNF-α–mediated toxicity and even lethality.

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An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma

Cited by 28 publications

References 0 publications

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

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