IFN-γ elicits macrophage autophagy via the p38 MAPK signaling pathway.
Autophagy is a major innate immune defense pathway in both plants and animals. In mammals, this cascade can be elicited by cytokines (IFN-γ) or pattern recognition receptors (TLRs and nucleotide-binding oligomerization domain-like receptors). Many signaling components in TLR- and nucleotide-binding oligomerization domain-like receptor-induced autophagy are now known; however, those involved in activating autophagy via IFN-γ remain to be elucidated. In this study, we engineered macrophages encoding a tandem fluorescently tagged LC3b (tfLC3) autophagosome reporter along with stably integrated short hairpin RNAs to demonstrate IFN-γ-induced autophagy required JAK 1/2, PI3K, and p38 MAPK but not STAT1. Moreover, the autophagy-related guanosine triphosphatase Irgm1 proved dispensable in both stable tfLC3-expressing RAW 264.7 and tfLC3-transduced Irgm1(-/-) primary macrophages, revealing a novel p38 MAPK-dependent, STAT1-independent autophagy pathway that bypasses Irgm1. These unexpected findings have implications for understanding how IFN-γ-induced autophagy is mobilized within macrophages for inflammation and host defense.
Osaka Prefecture University, Osaka, Japan. tm@vet.osakafu-u.ac.jp
Takeshi
T
Matsuzawa
Bae-Hoon
BH
Kim
Avinash R
AR
Shenoy
Shigeki
S
Kamitani
Masami
M
Miyake
John D
JD
Macmicking
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000502:physiology; D017930:Genes, Reporter / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010588:Phagosomes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
C096000:Ifi1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins