Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Anaphylactic degranulation by mast cells requires the mobilization of inflammasome components

Nature Immunology volume 25, pages 693–702 (2024)Cite this article

Subjects

Abstract

The inflammasome components NLRP3 and ASC are cytosolic proteins, which upon sensing endotoxins or danger cues, form multimeric complexes to process interleukin (IL)-1β for secretion. Here we found that antigen (Ag)-triggered degranulation of IgE-sensitized mast cells (MCs) was mediated by NLRP3 and ASC. IgE–Ag stimulated NEK7 and Pyk2 kinases in MCs to induce the deposition of NLRP3 and ASC on granules and form a distinct protein complex (granulosome) that chaperoned the granules to the cell surface. MCs deficient in NLRP3 or ASC did not form granulosomes, degranulated poorly in vitro and did not evoke systemic anaphylaxis in mice. IgE–Ag-triggered anaphylaxis was prevented by an NLRP3 inhibitor. In endotoxin-primed MCs, pro-IL-1β was rapidly packaged into granules after IgE–Ag stimulation and processed within granule remnants by proteases after degranulation, causing lethal anaphylaxis in mice. During IgE–Ag-mediated degranulation of endotoxin-primed MCs, granulosomes promoted degranulation, combined with exteriorization and processing of IL-1β, resulting in severe inflammation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Inflammasome components mediate MC degranulation following IgE–Ag stimulation.
Fig. 2: NLRP3 and ASC form a distinct complex with CD63 on MC granules.
Fig. 3: NEK7 and Pyk2 kinases are critical initiators of granulosome formation.
Fig. 4: Granulosomes facilitate MT polymerization and granule trafficking.
Fig. 5: NLRP3-targeting drug protects against anaphylaxis.
Fig. 6: Pro-IL-1β is released from intact granules following IgE–Ag activation of LPS-primed MCs.

Similar content being viewed by others

Data availability

Source data are available on figshare at https://doi.org/10.6084/m9.figshare.21856569.

References

  1. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell. 10, 417–426 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Swanson, K. V., Deng, M. & Ting, J. P.-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. He, Y., Zeng, M. Y., Yang, D., Motro, B. & Nunez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chung, I.-C. et al. Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis. Sci. Rep. 6, 36214 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guo, H., Callaway, J. B. & Ting, J. P.-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wen, H., Ting, J. P.-Y. & O’Neill, L. A. A role for the NLRP3 inflammasome in metabolic diseases–did Warburg miss inflammation? Nat. Immunol. 13, 352–357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Freeman, L. C. & Ting, J. P.-Y The pathogenic role of the inflammasome in neurodegenerative diseases. J. Neurochem. 136, 29–38 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Prochnicki, T. & Latz, E. Inflammasomes on the crossroads of innate immune recognition and metabolic control. Cell Metab. 26, 71–93 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Hughes, M. M. & O’Neill, L. A. J. Metabolic regulation of NLRP3. Immunol. Rev. 281, 88–98 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Akira, S., Misawa, T., Satoh, T. & Saitoh, T. Macrophages control innate inflammation. Diabetes Obes. Metab. 15, 10–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Abraham, S. N. & St John, A. L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10, 440–452 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gilfillan, A. M. & Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol. 6, 218–230 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Nakamura, Y. et al. Critical role for mast cells in interleukin-1beta-driven skin inflammation associated with an activating mutation in the nlrp3 protein. Immunity 37, 85–95 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin, C. et al. Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation. J. Clin. Invest. 127, 3913 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hogan, P. G., Lewis, R. S. & Rao, A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lorentz, A., Baumann, A., Vitte, J. & Blank, U. The SNARE machinery in mast cell secretion. Front. Immunol. 3, 143 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dwyer, D. F., Barrett, N. A., Austen, K. F. & Immunological Genome Project Consortium Expression profiling of constitutive mast cells reveals a unique identity within the immune system. Nat. Immunol. 17, 878–887 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nocka, K. et al. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. EMBO J. 9, 1805–1813 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Falcone, F. H., Wan, D., Barwary, N. & Sagi-Eisenberg, R. RBL cells as models for in vitro studies of mast cells and basophils. Immunol. Rev. 282, 47–57 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Galli, S. J. & Tsai, M. IgE and mast cells in allergic disease. Nat. Med. 18, 693–704 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Huber, M., Hughes, M. R. & Krystal, G. Thapsigargin-induced degranulation of mast cells is dependent on transient activation of phosphatidylinositol-3 kinase. J. Immunol. 165, 124–133 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Stehlik, C. et al. Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. J. Immunol. 171, 6154–6163 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Byrne, M. J. et al. Nek7 conformational flexibility and inhibitor binding probed through protein engineering of the R-spine. Biochem. J. 477, 1525–1539 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. He, H. et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat. Commun. 9, 2550 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hara, H. et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat. Immunol. 14, 1247–1255 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Okazaki, H., Zhang, J., Hamawy, M. M. & Siraganian, R. P. Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FcεRI signaling. J. Biol. Chem. 272, 32443–32447 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Cheung, S. M. & Ostergaard, H. L. Pyk2 controls integrin-dependent CTL migration through regulation of de-adhesion. J. Immunol. 197, 1945–1956 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Nishida, K. et al. FcεRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane. J. Cell Biol. 170, 115–126 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Draber, P., Sulimenko, V. & Draberova, E. Cytoskeleton in mast cell signaling. Front. Immunol. 3, 130 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liu, Y., Zhu, M., Nishida, K., Hirano, T. & Zhang, W. An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response. J. Exp. Med. 204, 93–103 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reck-Peterson, S. L., Redwine, W. B., Vale, R. D. & Carter, A. P. The cytoplasmic dynein transport machinery and its many cargoes. Nat. Rev. Mol. Cell Biol. 19, 382–398 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jiang, H. et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med. 214, 3219–3238 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Suurmond, J., Habets, K. L. L., Dorjee, A. L., Huizinga, T. W. & Toes, R. E. M. Expansion of Th17 cells by human mast cells is driven by inflammasome-independent IL-1beta. J. Immunol. 197, 4473–4481 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Kunder, C. A. et al. Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J. Exp. Med. 206, 2455–2467 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ronnberg, E., Melo, F. R. & Pejler, G. Mast cell proteoglycans. J. Histochem. Cytochem. 60, 950–962 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Thorne, P. S. et al. Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am. J. Respir. Crit. Care Med. 172, 1371–1377 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nat. Rev. Immunol. 8, 169–182 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Martin, R. K. et al. B1 Cell IgE impedes mast cell-mediated enhancement of parasite expulsion through B2 IgE blockade. Cell Rep. 22, 1824–1834 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Knight, P. A., Wright, S. H., Lawrence, C. E., Paterson, Y. Y. & Miller, H. R. Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mouse mast cell protease-1. J. Exp. Med. 192, 1849–1856 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Monaco, G. et al. RNA-seq signatures normalized by mRNA abundance allow absolute deconvolution of human immune cell types. Cell Rep. 26, 1627–1640 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Encalada, S. E., Szpankowski, L., Xia, C. H. & Goldstein, L. S. Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles. Cell 144, 551–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Efergan, A. et al. Rab12 regulates retrograde transport of mast cell secretory granules by interacting with the RILP–dynein complex. J. Immunol. 196, 1091–1101 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Wang, Z. et al. NLRP3 inflammasome and inflammatory diseases. Oxid. Med. Cell. Longev. 2020, 4063562 (2020).

    PubMed  PubMed Central  Google Scholar 

  46. Sakamaki, K. & Satou, Y. Caspases: evolutionary aspects of their functions in vertebrates. J. Fish. Biol. 74, 727–753 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Duke-NUS Medical School, Singapore, for their help with light microscopy imaging. We thank the SIgN Mutant Mouse Collection Core Facility for providing the mice. Funding for this study was provided by a block grant from Duke-NUS and NIGMS R01-GM144606.

Author information

Author notes

  1. Andrea Mencarelli

    Present address: Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  2. Hanif Javanmard Khameneh

    Present address: Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland

  3. These authors contributed equally: Andrea Mencarelli, Pradeep Bist.

Authors and Affiliations

  1. Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore, Singapore

    Andrea Mencarelli, Pradeep Bist & Soman N. Abraham

  2. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Hae Woong Choi & Soman N. Abraham

  3. Singapore Immunology Network (SIgN), Agency for Science and Research (A*Star), Singapore, Singapore

    Hanif Javanmard Khameneh

  4. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy

    Alessandra Mortellaro

  5. Department of Immunology, Duke University Medical Center, Durham, NC, USA

    Soman N. Abraham

  6. Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC, USA

    Soman N. Abraham

Authors
  1. Andrea Mencarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pradeep Bist
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hae Woong Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanif Javanmard Khameneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alessandra Mortellaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Soman N. Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A. Mencarelli, P.B. and S.N.A. conceived the study. A. Mencarelli, P.B. and H.W.C. performed experiments with advice from S.N.A. A. Mencarelli, P.B., H.J.K. and S.N.A. analyzed the data. A. Mortellaro supervised the in vivo experiments with mutant mice and contributed to data analysis. A. Mencarelli, P.B. and S.N.A. wrote the paper. All authors contributed to discussions and paper review. This work was supported by a block grant (to S.N.A.) from Duke-NUS Medical School, Singapore, and a SIgN core grant (A. Mortellaro) from A*STAR, Singapore.

Corresponding author

Correspondence to Soman N. Abraham.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Ioana Staicu, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Nlrp3−/− and Asc−/− BMMCs exhibit similar early signaling events as WT.

a, The impaired FcεRI-mediated degranulation observed in MCs ablated of Asc and Nlrp3 was also confirmed by flow cytometric analysis of the externalization of the granule membrane marker CD63 after IgE-Ag stimulation. b β-hexosaminidase release from IgE-Ag stimulated WT BMMCs silenced for siRNA targeting Control or Caspase-1. Western blot analysis of Caspase-1 protein levels. c, The BMMCs were subjected to toluidine blue staining which stains mature MC granule. Middle, flow cytometry analysis of BMMCs obtained from WT, Asc−/− Nlrp3−/− or Caspase1/11−/− mice showing that all BMMCs were similarly matured. The maturation markers employed were FcεRI, CD117, and avidin, respectively. d, Compared to WT BMMCs, Asc−/−, Caspase-1/11−/− and Nlrp3−/− BMMCs exhibit significantly reduced release of granule associated mediator’s TNF-α and histamine following IgE-Ag-mediated stimulation. Compared to WT BMMCs, Asc−/− and Nlrp3−/− BMMCs exhibited similar levels of secretion of de novo synthesized mediators PGD2 and IL-6. e, Western blots showing IgE-sensitized WT, Nlrp3−/− or Asc−/− BMMCs stimulated with Ag at different time points. The data are shown in a as mean ± s.d of two independent experiments, performed in triplicate, **P < 0.01, ***P < 0.005 (Ordinary one-way ANOVA multiple comparisons procedure), WT vs. Asc−/− and Nlrp3−/− BMMCs, for each time point indicated. Data are shown in b are mean ± s.e.m of one representative experiment, of three independent experiments with similar results, performed in triplicate; The images shown in c, are the representatives of four independent experiments, with similar results. The data are shown in c left, as mean ± s.d. of four independent experiments. The data are shown in d as mean ± s.d of two independent experiments, performed in duplicate or triplicate, **P < 0.01 (Ordinary one-way ANOVA multiple comparisons procedure), WT vs. Asc−/− and Nlrp3−/− BMMCs as indicated. Data shown in e are representative of three independent experiments.

Extended Data Fig. 2 The specificity of NLRP3 and ASC for MC granules CD63.

a, Immunofluorescence images of Asc−/− and Nlrp3−/− BMMCs co-stained with CD63 (green) and NLRP3 (red) or ASC (orange), respectively. Scale bar: 20 μm. b, Endogenous CD63 was immunoprecipitated from untreated or LPS/nigericin stimulated WT BMMCs. The association between CD63 and NLRP3, ASC, and Caspase-1 in different conditions was examined by Western blotting of the IP fractions. The proteins of interests in the total cell lysate (TCL) were also depicted to indicate that a similar level of CD63, NLRP3, ASC, and Caspase-1 protein present in each fraction. c, WT BMMCs were stimulated either with IgE-Ag or LPS/nigericin for the indicated time intervals, and the lysates were subjected to immunoprecipitation using NLRP3 antibody followed by immunoblotting with ASC, and NLRP3 antibodies. TCL was loaded as an input control. d, Myc-tagged ASC and Flag-tagged Caspase-1 with varying amounts of GFP-CD63 was overexpressed in HEK293T cells, and immunoprecipitated with Flag antibody revealing the binding of Caspase-1 with ASC by Western blotting of the IP fraction. The proteins of interests in the total cell lysate (TCL) was also depicted to indicate a similar level of CD63, ASC, and Caspase-1 protein present in each fraction. e, A diagrammatic representation of the spatial orientation of CD63 bound to either NLRP3 or ASC on granule membrane. Bottom, full length and its truncated forms of GFP-CD63 (1–6) used for immunoprecipitation assay with either Myc-tagged ASC or Flag-tagged NLRP3 in HEK293T cells. f, Western blots showing immunoprecipitation of GFP-tagged CD63 TM3 domain with varying amounts of ASC or NLRP3 in HEK293T cells. Two dark arrows indicate the varying concentration of NLRP3 or ASC expression plasmids. Immunofluorescence image data shown in a is representative of three independent experiments. The data shown in b is representative of two independent experiments. The data shown in c to e are representative of more than three independent experiments.

Extended Data Fig. 3 Signaling events downstream of Ca2+ axis is important for protein complex formation.

a, Western blots of immunoprecipitated CD63 with NLRP3, ASC, and tubulin from the lysates, sensitized with IgE and pretreated with or without BAPTA-AM, a chelator of intracellular calcium, following Ag stimulation in WT BMMCs. b, Western blots showing endogenous immunoprecipitation of NEK7 from WT and Asc−/− BMMCs in response to IgE-Ag stimulation as indicated. The proteins of interests in the total cell lysate (TCL) was also depicted to indicate that similar level of NLRP3, NEK7, and ASC protein present in each fraction. c, Western blots showing the status of Pyk2 and ASC activation in IgE-Ag-stimulated WT and Nlrp3−/− BMMCs. c, ASC is located downstream of Pyk2. Western blots showing the status of Pyk2 and ASC activation in IgE-Ag-stimulated WT and Nlrp3−/− BMMCs. Data presented in a to c are representative of three or more independent experiments.

Extended Data Fig. 4 Distribution of tubulin and dynein on MC granules.

a, Quantitative analysis of α-tubulin in WT, Nlrp3−/− and Asc−/− BMMCs following IgE-Ag stimulation. The α-tubulin signals were measured in each cell with a radius of 12-16 μm using ZEN Imaging Software (Zeiss). Background fluorescence using a circle of the corresponding size was subtracted from each measurement. b, Densitometric analysis of Fig. 4b tubulin protein intensity from WT, Nlrp3−/−, Asc−/−, and Caspase-1/11−/− BMMCs following IgE-Ag stimulation. c, β-hexosaminidase release from untreated or IgE-Ag stimulation in WT, Nlrp3−/−, and Asc−/−, BMMCs pre-treated with varying concentrations of Rhosin, a drug that targets RhoA GTPase. d, Western blots showing immunoprecipitation of NLRP3 with dynein from WT BMMCs primed with LPS and subsequently challenged with varying amounts of nigericin. e, Representative confocal microscopy images co-stained for CD63 (green) and tubulin (red). f, CD63 (green) and dynein (light yellow) in WT BMMCs following IgE-Ag stimulation at different time points. Scale bar: 20 μm. f, Densitometry analysis of Fig. 4f protein (GFP-CD63) intensity from siRNAs (control, Nlrp3, and Asc) of the plasma membrane. Data shown in a are mean ± s.d. of one representative experiments, n = 6 cells/group. ***P < 0.001 (Ordinary one-way ANOVA multiple comparisons procedure). Data shown in b are densitometry analysis of Fig. 4b and representatives of three independent experiments. Data shown in c are mean ± s.d of four independent experiments, performed in triplicate, ***P < 0.005 (Ordinary one-way ANOVA multiple comparisons procedure), vs. WT cells stimulated with IgE/Ag with no Rhosin. Data shown in d is representative of two independent experiments. Immunofluorescence images shown in e and f are representative of two independent experiments with similar results.

Extended Data Fig. 5 Schematic model showing a cascade of signaling events involved in the formation of granulosome complex during anaphylactic degranulation in MCs.

(1) Aggregation of FcεRI by antigen triggers a cascade of mast cell signaling events including the activation of phospholipase C (PLCγ) which in turn increases the intracellular Ca2+ levels facilitating the recruitment of two critical kinases, NEK7 and Pyk2. NEK7 kinase binds to NLRP3 and promotes its dimerization, whereas Pyk2 kinase mediates ASC phosphorylation and its dimerization. In many cases, following IgE-Ag activation, granules fuse with each other to form larger compound granules within the mast cell. Thereafter, dimerized NLRP3 and ASC deposit on compound granules enabling a conformational change that allows the oligomerization of CD63 to facilitate the formation of a multiprotein complex ‘granulosome’ comprising NLRP3, ASC, and CD63 (boxed figure) (2). Subsequent to the formation of a microtubule-organizing center (MTOC), a motor protein, dynein is recruited to the granulosome by specifically binding to NLRP3, which then moves along with MTs (microtubules) to the cell periphery where cytosolic compound granules are exteriorized (2). If the MCs are pre-exposed to endotoxin such as LPS, which induces NF-κB-mediated expression of pro-IL-1β(1), thereafter, following IgE-Ag stimulation, pro-IL-1β is rapidly incorporated into the compound granules and when granules are exteriorized, they contain bulk amounts of pro-IL-1β and chymase. In the external medium, pro-IL-1β is processed into mature IL-1β by chymase within the granule remnants (3) before both IL-1β and chymase are released into the external medium. Created with BioRender.com.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mencarelli, A., Bist, P., Choi, H.W. et al. Anaphylactic degranulation by mast cells requires the mobilization of inflammasome components. Nat Immunol 25, 693–702 (2024). https://doi.org/10.1038/s41590-024-01788-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-024-01788-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing