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The innate immune system employs germline-encoded pattern recognition receptors (PRRs) that can detect pathogens and initiate the immune response. The Toll-like receptors (TLRs) are the best studied PRRs and they act by initiating an intracellular signaling cascade that is dependent on the adaptor proteins MyD88 and TRIF. This response activates the critical transcription factors NF-κB and IRF3, and functions to prime both the innate and adaptive immune effector cells for pathogen clearance. Macrophages are one of the major effector cell types of innate immunity. They help clear extracellular infections by phagocytosis and eventual phagosome–lysosome fusion, and intracellular infections by enclosing microbes in autophagic vesicles for delivery to the lysosome. Initiation of autophagy requires phosphatidylinositol 3-phosphate [PtdIns(3)P], which is generated by the phosphatidylinositol 3-kinase class III (PtdIns3KC3/Vps34) complex. This chapter discusses the detailed molecular mechanisms through which TLR signaling primes macrophages for intracellular pathogen clearance by initiating autophagy. We focus on Beclin 1, a key component of the PtdIsn3KC3 complex, which is recruited to the TLR signalosome upon TLR stimulation and subsequently posttranslationally modified to disrupt its binding with its inhibitor, Bcl-2.

Inflammation is an important physiological response to noxious stimuli, but unchecked inflammation is pathophysiological and can result in tissue destruction and autoimmune disease. Inflammasomes are large multimeric signaling complexes of the innate immune system involved in the proteolytic cleavage and activation of interleukin-1 beta (IL-1β) and IL-18. Inflammasome signaling is a key early step in generating the inflammatory response as IL-1β is a critical cytokine in mediating systemic inflammation and has a variety of downstream effects. Aberrant inflammasome activation is the basis of many human autoinflammatory diseases, thus delineation of feedback loops regulating inflammasome signaling is of great importance to understanding autoinflammatory conditions. Autophagy is a conserved degradation pathway that delivers damaged organelles and aged protein complexes to the lysosome for destruction. It evolved both as a cellular recycling system and as a quality control system to ensure cellular homeostasis. This chapter covers the dynamic interplay between inflammasome activation and autophagy induction, with a specific focus on the cellular and molecular mechanisms by which autophagy feedback inhibits inflammasome signaling.