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:

Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1β production

Cellular & Molecular Immunology volume 18, pages 2024–2039 (2021)Cite this article

Subjects

Abstract

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex plays a role in both canonical and noncanonical autophagy, key processes that control immune-cell responsiveness to a variety of stimuli. Our previous studies found that PIK3C3 is a critical regulator that controls the development, homeostasis, and function of dendritic and T cells. In this study, we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice. We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex (MHC) class I and class II molecules. In addition, myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4. Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery (initiation/nucleation) of the classical autophagy pathway. Consequently, myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis (EAE), a primarily CD4+ T-cell-mediated mouse model of multiple sclerosis (MS). This disease protection was associated with reduced accumulation of myelin-specific CD4+ T cells in the central nervous system and decreased myeloid cell IL-1β production. Further, administration of SAR405, a selective PIK3C3 inhibitor, delayed disease progression. Collectively, our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE. Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.

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: Characterization of autophagy and CD11b+ cells during EAE.
Fig. 2: Single-cell autophagy gene transcriptome analysis of CNS inflammation.
Fig. 3: Effects of myeloid-specific Pik3c3 ablation on autophagy and immune parameters.
Fig. 4: Myeloid-specific Pik3c3 deficiency modulates macrophage phenotypes.
Fig. 5: Pik3c3 deficiency in myeloid cells attenuates the severity of active and passive EAE.
Fig. 6: Pik3c3-deficient macrophages display defective efferocytosis.
Fig. 7: Pik3c3 deficiency in myeloid cells inhibits EAE-induced IL-1β production in the CNS.
Fig. 8: SAR405 treatment delays the onset of EAE.

Similar content being viewed by others

References

  1. Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu Rev. Cell Dev. Biol. 27, 107–132 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Ktistakis, N. T. & Tooze, S. A. Digesting the expanding mechanisms of autophagy. Trends Cell Biol. 26, 624–635 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jaber, N. & Zong, W. X. Class III PI3K Vps34: essential roles in autophagy, endocytosis, and heart and liver function. Ann. N. Y. Acad. Sci. 1280, 48–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Backer, J. M. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J. 410, 1–17 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Boyle, K. B. & Randow, F. Rubicon swaps autophagy for LAP. Nat. Cell Biol. 17, 843–845 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Heckmann, B. L. et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine alzheimer’s disease. Cell 178, 536–551.e14 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519–530 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Itakura, E., Kishi, C., Inoue, K. & Mizushima, N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19, 5360–5372 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou, X. et al. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proc. Natl Acad. Sci. U.S.A. 107, 9424–9429 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McLeod, I. X., Zhou, X., Li, Q. J., Wang, F. & He, Y. W. The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Ralpha surface expression. J. Immunol. 187, 5051–5061 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Willinger, T. & Flavell, R. A. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proc. Natl Acad. Sci. U.S.A. 109, 8670–8675 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parekh, V. V. et al. Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps34. J. Immunol. 190, 5086–5101 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Jaber, N. et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl Acad. Sci. U.S.A. 109, 2003–2008 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Devereaux, K. et al. Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PloS ONE 8, e76405 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bechtel, W. et al. The class III phosphatidylinositol 3-kinase PIK3C3/VPS34 regulates endocytosis and autophagosome-autolysosome formation in podocytes. Autophagy 9, 1097–1099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bechtel, W. et al. Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J. Am. Soc. Nephrology 24, 727–743 (2013).

    Article  CAS  Google Scholar 

  18. Morishita, H. et al. Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J. Biol. Chem. 288, 11436–11447 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Parekh, V. V. et al. Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8alpha(+) dendritic cells. Proc. Natl Acad. Sci. U.S.A. 114, E6371–E6380 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang, G. et al. Autophagy-related protein PIK3C3/VPS34 controls T cell metabolism and function. Autophagy 1–12, https://doi.org/10.1080/15548627.2020.1752979 (2020).

  21. Alirezaei, M. et al. Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis. Autophagy 5, 152–158 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Patergnani, S. et al. Autophagy and mitophagy elements are increased in body fluids of multiple sclerosis-affected individuals. J. Neurol., Neurosurg., Psychiatry 89, 439–441 (2018).

    Article  Google Scholar 

  23. Bhattacharya, A., Parillon, X., Zeng, S., Han, S. & Eissa, N. T. Deficiency of autophagy in dendritic cells protects against experimental autoimmune encephalomyelitis. J. Biol. Chem. 289, 26525–26532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Buckley, K. M. et al. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp. Transl. Stroke Med. 6, 8 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bonam, S. R., Wang, F. & Muller, S. Autophagy: a new concept in autoimmunity regulation and a novel therapeutic option. J. Autoimmun. 94, 16–32 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Zhu, B. et al. CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. J. Immunol. 179, 5228–5237 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Li, L., Wang, Z. V., Hill, J. A. & Lin, F. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. J. Am. Soc. Nephrol. 25, 305–315 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Jordao, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, https://doi.org/10.1126/science.aat7554 (2019).

  29. Abram, C. L., Roberge, G. L., Hu, Y. & Lowell, C. A. Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J. Immunol. Methods 408, 89–100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ferro, A. et al. Inhibition of NF-kappaB signaling in IKKbetaF/F;LysM Cre mice causes motor deficits but does not alter pathogenesis of Spinocerebellar ataxia type 1. PloS ONE 13, e0200013 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Pulido-Salgado, M. et al. Myeloid C/EBPbeta deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis. J. Neuroinflammation 14, 54 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Abdel Fattah, E., Bhattacharya, A., Herron, A., Safdar, Z. & Eissa, N. T. Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency. J. Immunol. 194, 5407–5416 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Kanayama, M., He, Y. W. & Shinohara, M. L. The lung is protected from spontaneous inflammation by autophagy in myeloid cells. J. Immunol. 194, 5465–5471 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Kanayama, M., Danzaki, K., He, Y. W. & Shinohara, M. L. Lung inflammation stalls Th17-cell migration en route to the central nervous system during the development of experimental autoimmune encephalomyelitis. Int. Immunol. 28, 463–469 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, Y. T. et al. Select autophagy genes maintain quiescence of tissue-resident macrophages and increase susceptibility to Listeria monocytogenes. Nat. Microbiol. 5, 272–281 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pua, H. H., Guo, J., Komatsu, M. & He, Y. W. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J. Immunol. 182, 4046–4055 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Riffelmacher, T., Richter, F. C. & Simon, A. K. Autophagy dictates metabolism and differentiation of inflammatory immune cells. Autophagy 14, 199–206 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Vats, D. et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wong, K. et al. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proc. Natl Acad. Sci. U.S.A. 107, 8712–8717 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yang, G., Driver, J. P. & Van Kaer, L. The role of autophagy in iNKT cell development. Front. Immunol. 9, 2653 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893–906 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bhattacharya, A. et al. Autophagy is required for neutrophil-mediated inflammation. Cell Rep. 12, 1731–1739 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Shi, J., Hua, L., Harmer, D., Li, P. & Ren, G. Cre driver mice targeting macrophages. Methods Mol. Biol. 1784, 263–275 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Orthgiess, J. et al. Neurons exhibit Lyz2 promoter activity in vivo: Implications for using LysM-Cre mice in myeloid cell research. Eur. J. Immunol. 46, 1529–1532 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Jiang, Z., Jiang, J. X. & Zhang, G. X. Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol. Lett. 160, 17–22 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Slavin, A. J. et al. Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity. J. Clin. Invest. 108, 1133–1139 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sosa, R. A., Murphey, C., Ji, N., Cardona, A. E. & Forsthuber, T. G. The kinetics of myelin antigen uptake by myeloid cells in the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol. 191, 5848–5857 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Yogev, N. et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 37, 264–275 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Isaksson, M., Lundgren, B. A., Ahlgren, K. M., Kampe, O. & Lobell, A. Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE. Eur. J. Immunol. 42, 2555–2563 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. U.S.A. 108, 17396–17401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hovelmeyer, N. et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J. Immunol. 175, 5875–5884 (2005).

    Article  PubMed  Google Scholar 

  54. Wu, M. Y. et al. PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation. Autophagy 1–16, https://doi.org/10.1080/15548627.2020.1741332 (2020).

  55. Konishi, A., Arakawa, S., Yue, Z. & Shimizu, S. Involvement of Beclin 1 in engulfment of apoptotic cells. J. Biol. Chem. 287, 13919–13929 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Levesque, S. A. et al. Myeloid cell transmigration across the CNS vasculature triggers IL-1beta-driven neuroinflammation during autoimmune encephalomyelitis in mice. J. Exp. Med. 213, 929–949 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pare, A. et al. IL-1beta enables CNS access to CCR2(hi) monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells. Proc. Natl Acad. Sci. U.S.A. 115, E1194–E1203 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Olcum, M., Tastan, B., Kiser, C., Genc, S. & Genc, K. Microglial NLRP3 inflammasome activation in multiple sclerosis. Adv. Protein Chem. Struct. Biol. 119, 247–308 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Kobayashi, N. et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27, 927–940 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Galluzzi, L. & Green, D. R. Autophagy-independent functions of the autophagy machinery. Cell 177, 1682–1699 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Van Kaer, L., Postoak, J. L., Wang, C., Yang, G. & Wu, L. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-019-0221-5 (2019).

  64. Yin, L. et al. Autophagy-related gene16L2, a potential serum biomarker of multiple sclerosis evaluated by bead-based proteomic technology. Neurosci. Lett. 562, 34–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Igci, M. et al. Gene expression profiles of autophagy-related genes in multiple sclerosis. Gene 588, 38–46 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Kimmey, J. M. et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528, 565–569 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456, 264–268 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Kimura, T. et al. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J. 36, 42–60 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Dupont, N. et al. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. EMBO J. 30, 4701–4711 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cain, D. W. et al. Identification of a tissue-specific, C/EBPbeta-dependent pathway of differentiation for murine peritoneal macrophages. J. Immunol. 191, 4665–4675 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the authors’ lab was supported by grants from the NIH (AI139046 to L.V.K. and 1ZIAES10328601 to J.M.) and the National Multiple Sclerosis Society (60006625 to L.V.K.). Core Services were performed through the Vanderbilt Digestive Disease Research Center (NIH grant P30DK058404), the Vanderbilt Ingram Cancer Center (NIH grant P30CA68485), and the Vanderbilt Diabetes Research and Training Center (NIH grant P60DK020593). J.L.P. was supported by predoctoral NIH training grants (T32HL069765 and T32AR059039).

Author information

Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Guan Yang, Wenqiang Song, J. Luke Postoak, Lan Wu & Luc Van Kaer

  2. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Jielin Xu & Feixiong Cheng

  3. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA

    Feixiong Cheng

  4. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Feixiong Cheng

  5. Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA

    Jennifer Martinez

  6. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Jianhua Zhang

  7. Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35233, USA

    Jianhua Zhang

Authors
  1. Guan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenqiang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jielin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Luke Postoak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Feixiong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jennifer Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianhua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Luc Van Kaer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.Y. and L.V.K designed research; G.Y., W.S., J.X., J.L.P., F.C., and L.W. performed research; G.Y. analyzed data; J.M. and J.Z. contributed new reagents/analytic tools; G.Y. and L.V.K. wrote the paper.

Corresponding author

Correspondence to Luc Van Kaer.

Ethics declarations

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, G., Song, W., Xu, J. et al. Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1β production. Cell Mol Immunol 18, 2024–2039 (2021). https://doi.org/10.1038/s41423-020-00589-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-00589-1

Keywords

Search

Advanced search

Quick links