Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

Flach, Tracy L.; Ng, Gilbert; Hari, Aswin; Desrosiers, Melanie D.; Zhang, Ping; Ward, Sandra; Seamone, Mark E.; Vilaysane, Akosua; Mucsi, Ashley D.; Fong, Yin; Prenner, Elmar J.; Ling, Chen; Tschopp, Jürg; Muruve, Daniel A.; Amrein, Matthias; Shi, Yan

doi:10.1038/nm.2306

Cited by 351 publications

(313 citation statements)

References 44 publications

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“…If future studies determine that the adjuvant properties of chitosan are inflammasome-dependent, then formulations consisting of particles small enough to be phagocytosed would likely lead to maximum effectiveness. Interestingly, the commonly used adjuvant alum also stimulates the NLRP3 inflammasome (27,53,54), although recent studies have suggested that the ability of alum to activate the inflammasome is not required for its adjuvanticity (55). Chitosan has also been utilized to encapsulate DNA (56), and the primary amines of chitosan can be exploited to conjugate antigens, thus allowing direct delivery into cells.…”

Section: Discussionmentioning

confidence: 99%

Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis

Bueter

Lee

Rathinam

et al. 2011

Journal of Biological Chemistry

165

126

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Chitin is an abundant polysaccharide found in fungal cell walls, crustacean shells, and insect exoskeletons. The immunological properties of both chitin and its deacetylated derivative chitosan are of relevance because of frequent natural exposure and their use in medical applications. Depending on the preparation studied and the end point measured, these compounds have been reported to induce allergic responses, inflammatory responses, or no response at all. We prepared highly purified chitosan and chitin and examined the capacity of these glycans to stimulate murine macrophages to release the inflammasome-associated cytokine IL-1β. We found that although chitosan was a potent NLRP3 inflammasome activator, acetylation of the chitosan to chitin resulted in a near total loss of activity. The size of the chitosan particles played an important role, with small particles eliciting the greatest activity. An inverse relationship between size and stimulatory activity was demonstrated using chitosan passed through size exclusion filters as well as with chitosan-coated beads of defined size. Partial digestion of chitosan with pepsin resulted in a larger fraction of small phagocytosable particles and more potent inflammasome activity. Inhibition of phagocytosis with cytochalasin D abolished the IL-1β stimulatory activity of chitosan, offering an explanation for why the largest particles were nearly devoid of activity. Thus, the deacetylated polysaccharide chitosan potently activates the NLRP3 inflammasome in a phagocytosis-dependent manner. In contrast, chitin is relatively inert.

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Section: Discussionmentioning

confidence: 99%

Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis

Bueter

Lee

Rathinam

et al. 2011

Journal of Biological Chemistry

165

126

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“…Thus, in this model we envision direct interaction of macrophages with the biomaterial surface. Interestingly, microparticles like alum can also induce syk activation in DCs, which raises the possibility that these cells have a similar ability to respond to biomaterials (20). However, the DC response to alum was shown to be caspase-1 independent, implicating the involvement of a separate pathway.…”

Section: Discussionmentioning

confidence: 99%

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

Malik

Hoque

Ouyang

et al. 2011

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

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Implantation of biomaterials and devices into soft tissues leads to the development of the foreign body response (FBR), which can interfere with implant function and eventually lead to failure. The FBR consists of overlapping acute and persistent inflammatory phases coupled with collagenous encapsulation and currently there are no therapeutic options. Initiation of the FBR involves macrophage activation, proceeding to giant cell formation, fibroblast activation, and collagen matrix deposition. Despite the recognition of this sequence of events, the molecular pathways required for the FBR have not been elucidated. We have identified that the acute inflammatory response to biomaterials requires nucleotide-binding domain and leucine-rich repeat-containing 3 (Nlrp3), apoptosis-associated speck-like protein containing CARD (Asc), and caspase-1, as well as plasma membrane cholesterol, and Syk signaling. Full development of the FBR is dependent on Asc and caspase-1, but not Nlrp3. The common antiinflammatory drug aspirin can reduce inflammasome activation and significantly reduce the FBR. Taken together, these findings expand the role of the inflammasome from one of sensing damage associated molecular patterns (DAMPs) to sensing all particulate matter irrespective of size. In addition, implication of the inflammasome in biomaterial recognition identifies key pathways, which can be targeted to limit the FBR.

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“…Kool et al (2) first demonstrated in mice that injection of alum results in the release of uric acid, an endogenous danger signal, which then activates inflammatory dendritic cells (DCs) to prime CD4 + T cells. Shortly after, Flach et al (3) showed that alum crystals directly interact with membrane lipids on DCs, initiating a signaling cascade that increases cell surface levels of LFA-1 and ICAM-1, which, in turn, enables CD4 + T cells to bind with higher affinity to the DCs. Some studies suggested that the release of dsDNA from damaged and dying host cells, which is induced by alum injection, may contribute to priming of Th2 CD4 + T cells (4,5) and enhance MHC class II-mediated Ag presentation, prolonging CD4 + T cell interactions with DCs (5).…”

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confidence: 99%

The Syk–NFAT–IL-2 Pathway in Dendritic Cells Is Required for Optimal Sterile Immunity Elicited by Alum Adjuvants

Khameneh

Spreafico

et al. 2017

The Journal of Immunology

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Despite a long history and extensive usage of insoluble aluminum salts (alum) as vaccine adjuvants, the molecular mechanisms underpinning Ag-specific immunity upon vaccination remain unclear. Dendritic cells (DCs) are crucial initiators of immune responses, but little is known about the molecular pathways used by DCs to sense alum and, in turn, activate T and B cells. In this article, we show that alum adjuvanticity requires IL-2 specifically released by DCs, even when T cell secretion of IL-2 is intact. We demonstrate that alum, as well as other sterile particulates, such as uric acid crystals, induces DCs to produce IL-2 following initiation of actin-mediated phagocytosis that leads to Src and Syk kinase activation, Ca 2+ mobilization, and calcineurin-dependent activation of NFAT, the master transcription factor regulating IL-2 expression. Using chimeric mice, we show that DC-derived IL-2 is required for maximal Ag-specific proliferation of CD4 + T cells and optimal humoral responses following alum-adjuvanted immunization. These data identify DC-derived IL-2 as a key mediator of alum adjuvanticity in vivo and the Src-Syk pathway as a potential leverage point in the rational design of novel adjuvants.

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Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

Cited by 351 publications

References 44 publications

Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis

Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

The Syk–NFAT–IL-2 Pathway in Dendritic Cells Is Required for Optimal Sterile Immunity Elicited by Alum Adjuvants

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