TY - JOUR
T1 - Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes
AU - Wang, Ya Ting
AU - Sansone, Amy
AU - Smirnov, Asya
AU - Stallings, Christina L.
AU - Orvedahl, Anthony
N1 - Funding Information:
Acknowledgments: We thank Diane Bender for assistance with Luminex assays. We thank Darren Kreamalmeyer for assistance with mouse husbandry. Funding: A.O., T32 AI106688 (NIAID); Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number K08AI144033. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health; supported, in part, by Research Grant No. SPR-2019-2 from the Society for Pediatric Research; and supported, in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University, Immunomonitoring Laboratory. Work was supported by NIH AI132697, NIH AI142784, and a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award to C.L.S.
Funding Information:
The work was supported by the National Institute of Allergy and Infectious Diseases [T32AI106688]; Society for Pediatric Research [SPR-2019-2]; National Institute of Allergy and Infectious Diseases [1K08AI144033]. Funding: A.O., T32 AI106688 (NIAID); Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number K08AI144033. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health; supported, in part, by Research Grant No. SPR-2019-2 from the Society for Pediatric Research. Work was supported by NIH AI132697, NIH AI142784, and a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award to C.L.S. Acknowledgments: We thank Diane Bender for assistance with Luminex assays. We thank Darren Kreamalmeyer for assistance with mouse husbandry. Supported in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University, Immunomonitoring Laboratory.
Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - Macroautophagy/autophagy regulates inflammation via multiple mechanisms, including lysosomal degradation of specific cellular components. Certain autophagy gene “cassettes” also participate in non-canonical processes to mediate important biological activities. While select autophagy genes in myeloid cells have been implicated in protecting mice in models of cytokine storm syndromes (CSS), a more extensive genetic analysis of the autophagy pathway for this disorder has not been reported to date. We determined that multiple canonical autophagy genes in the myeloid compartment protected against fatal disease from both intravenous TNF and intraperitoneal LPS, with the notable exception that Atg14 was dispensable for the latter. Serum cytokine analyses and genetic crosses further revealed distinct mechanisms contribute to the hypersensitivity of autophagy gene-deficient mice in these CSS models. Surprisingly, TNF was dispensable for the increased mortality of myeloid 5-deficient mice challenged with LPS. Tissue-specific ablation of Atg5 in cells expressing ITGAX/CD11c and LYZ2/LYSM, but not S100A8/MRP8, defined a myeloid subset that protected against TNF, while protection against LPS was conferred by Atg5 in a distinct subset of LYZ2-expressing cells. Together, this study identifies autophagy gene sets and specific cell types that protect against fatal inflammation due to CSS, highlighting important differences in two commonly used murine models of the disorder. Abbreviations: ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.
AB - Macroautophagy/autophagy regulates inflammation via multiple mechanisms, including lysosomal degradation of specific cellular components. Certain autophagy gene “cassettes” also participate in non-canonical processes to mediate important biological activities. While select autophagy genes in myeloid cells have been implicated in protecting mice in models of cytokine storm syndromes (CSS), a more extensive genetic analysis of the autophagy pathway for this disorder has not been reported to date. We determined that multiple canonical autophagy genes in the myeloid compartment protected against fatal disease from both intravenous TNF and intraperitoneal LPS, with the notable exception that Atg14 was dispensable for the latter. Serum cytokine analyses and genetic crosses further revealed distinct mechanisms contribute to the hypersensitivity of autophagy gene-deficient mice in these CSS models. Surprisingly, TNF was dispensable for the increased mortality of myeloid 5-deficient mice challenged with LPS. Tissue-specific ablation of Atg5 in cells expressing ITGAX/CD11c and LYZ2/LYSM, but not S100A8/MRP8, defined a myeloid subset that protected against TNF, while protection against LPS was conferred by Atg5 in a distinct subset of LYZ2-expressing cells. Together, this study identifies autophagy gene sets and specific cell types that protect against fatal inflammation due to CSS, highlighting important differences in two commonly used murine models of the disorder. Abbreviations: ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.
KW - Autophagy
KW - cytokine storm syndrome
KW - interferon gamma
KW - myeloid cells
KW - tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=85137737714&partnerID=8YFLogxK
U2 - 10.1080/15548627.2022.2116675
DO - 10.1080/15548627.2022.2116675
M3 - Article
C2 - 36056542
AN - SCOPUS:85137737714
SN - 1554-8627
VL - 19
SP - 1114
EP - 1127
JO - Autophagy
JF - Autophagy
IS - 4
ER -