Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation

James Harris, Michelle L Hartman, Caitrionna Jane Roche, Shijuan Grace Zeng, Amy O'Shea, Fiona A Sharp, Eimear M Lambe, Emma Creagh, Douglas Taylor Golenbock, Jurg Tschopp, Hardy Kornfeld, Katherine A Fitzgerald, Ed C Lavelle

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1beta secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1beta in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1beta was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1beta and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1beta by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1beta in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1beta through at least two separate mechanisms: by targeting pro-IL-1beta for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.
Original languageEnglish
Pages (from-to)9587 - 9597
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number11
DOIs
Publication statusPublished - 2011

Cite this

Harris, J., Hartman, M. L., Roche, C. J., Zeng, S. G., O'Shea, A., Sharp, F. A., ... Lavelle, E. C. (2011). Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. Journal of Biological Chemistry, 286(11), 9587 - 9597. https://doi.org/10.1074/jbc.M110.202911
Harris, James ; Hartman, Michelle L ; Roche, Caitrionna Jane ; Zeng, Shijuan Grace ; O'Shea, Amy ; Sharp, Fiona A ; Lambe, Eimear M ; Creagh, Emma ; Golenbock, Douglas Taylor ; Tschopp, Jurg ; Kornfeld, Hardy ; Fitzgerald, Katherine A ; Lavelle, Ed C. / Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 11. pp. 9587 - 9597.
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abstract = "Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1beta secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1beta in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1beta was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1beta and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1beta by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1beta in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1beta through at least two separate mechanisms: by targeting pro-IL-1beta for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.",
author = "James Harris and Hartman, {Michelle L} and Roche, {Caitrionna Jane} and Zeng, {Shijuan Grace} and Amy O'Shea and Sharp, {Fiona A} and Lambe, {Eimear M} and Emma Creagh and Golenbock, {Douglas Taylor} and Jurg Tschopp and Hardy Kornfeld and Fitzgerald, {Katherine A} and Lavelle, {Ed C}",
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Harris, J, Hartman, ML, Roche, CJ, Zeng, SG, O'Shea, A, Sharp, FA, Lambe, EM, Creagh, E, Golenbock, DT, Tschopp, J, Kornfeld, H, Fitzgerald, KA & Lavelle, EC 2011, 'Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation' Journal of Biological Chemistry, vol. 286, no. 11, pp. 9587 - 9597. https://doi.org/10.1074/jbc.M110.202911

Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. / Harris, James; Hartman, Michelle L; Roche, Caitrionna Jane; Zeng, Shijuan Grace; O'Shea, Amy; Sharp, Fiona A; Lambe, Eimear M; Creagh, Emma; Golenbock, Douglas Taylor; Tschopp, Jurg; Kornfeld, Hardy; Fitzgerald, Katherine A; Lavelle, Ed C.

In: Journal of Biological Chemistry, Vol. 286, No. 11, 2011, p. 9587 - 9597.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation

AU - Harris, James

AU - Hartman, Michelle L

AU - Roche, Caitrionna Jane

AU - Zeng, Shijuan Grace

AU - O'Shea, Amy

AU - Sharp, Fiona A

AU - Lambe, Eimear M

AU - Creagh, Emma

AU - Golenbock, Douglas Taylor

AU - Tschopp, Jurg

AU - Kornfeld, Hardy

AU - Fitzgerald, Katherine A

AU - Lavelle, Ed C

PY - 2011

Y1 - 2011

N2 - Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1beta secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1beta in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1beta was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1beta and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1beta by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1beta in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1beta through at least two separate mechanisms: by targeting pro-IL-1beta for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.

AB - Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1beta secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1beta in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1beta was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1beta and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1beta by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1beta in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1beta through at least two separate mechanisms: by targeting pro-IL-1beta for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.

UR - http://www.ncbi.nlm.nih.gov/pubmed/21228274

U2 - 10.1074/jbc.M110.202911

DO - 10.1074/jbc.M110.202911

M3 - Article

VL - 286

SP - 9587

EP - 9597

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 11

ER -