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ABSTRACTMacroautophagy/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 Atg14was 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 Atg5in 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 Atg5in 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.AbbreviationsATG5: 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.

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Autophagy is an evolutionarily ancient pathway for survival during different forms of cellular stress, including infection with viruses and other intracellular pathogens. Autophagy may protect against viral infection through degradation of viral components (xenophagy), by promoting the survival or death of infected cells, through delivery of Toll-like receptor (TLR) ligands to endosomes to activate innate immunity, or by feeding antigens to MHC class II compartments to activate adaptive immunity. Given this integral role of autophagy in innate and adaptive antiviral immunity, selective pressure likely promoted the emergence of escape mechanisms by pathogenic viruses. This review will briefly summarize the current understanding of autophagy as an antiviral pathway, and then discuss strategies that viruses may utilize to evade this host defense mechanism.

The first Keystone Symposium on Autophagy in Health and Disease was held in Monterey, a scenic city on the Pacific coast in central California, April 15-20, 2007. The symposium brought together approximately 280 participants, from basic researchers to physicians and journalists. The meeting was composed of a joint keynote session with the meeting “Apoptotic and Non-Apoptotic Cell Death Pathways”, and eight plenary sessions, covering the molecular mechanisms of autophagy and many emerging concepts and functions of autophagy in organelle degradation, physiological regulation, cell death and survival, and disease. Three afternoon workshops focused on short talks selected from the posters, and a special discussion session led by experts dealt with techniques and concerns regarding experimental detection of autophagy. The symposium highlighted autophagy as a potential therapeutic target in a wide range of diseases, including cancer, microbial infection, myopathies and neurodegenerative disorders.