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Abstract

Inflammation is a crucial mechanism of innate immune response. Macrophages and neutrophils recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), undergoing a complex set of signaling interactions to release pro-inflammatory cytokines (most notably that prompt inflammatory response. To mediate innate immune response, pattern-recognition receptors (PRRs) recognize a broad range of markers of infection, stress, and damage. PRRs include membrane-bound receptors such as Toll-like receptors (TLRs), the interleukin receptors (ILRs), and the tumor necrosis factor receptors 1 (TNF-R1) and 2 (TNF-R2). Upon binding of extracellular ligands, these PRRs activate intracellular signaling events, such as activation of NFκB, a transcription factor that upregulates expression of a wide variety of stress-response genes, or through post-translational modification such as activation of c-Jun amino-terminal kinase (JNK) [2] to effect inflammatory response. Within the cytoplasm, inflammatory ligands bind and activate intracellular PRRs that combine with a variety of associated factors to form large cytoplasmic scaffolding assemblies that integrate inflammatory activation and activate secretion of the major cytokines IL-1β and IL-18 by binding and activating caspase-1 [3] (Figure 1). These cytoplasmic PRRs, classed as nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs), recognize a wide variety of intracellular inflammatory stimuli. Four classes of NLRs (NLRP1, NLRP3, NLRC4 and AIM2) share in common a nucleotide-binding oligomerization domain, and have demonstrated an ability to form large oligomeric inflammasome complexes in the cytoplasm [4]. While each of the four sense a variety of inflammatory signals to mediate caspase-dependent activation of inflammation, the NLRP3 inflammasome is the best characterized.Plasma membrane PRRs TLR, ILR, and TNF-R (red boxes) bind cytokines and extracellular ligands, activating NFκB and JNK, which activate nuclear transcription of cellular stress factors, particularly NLRP3. NLRP3 (blue), ASC (gold), and caspase-1 (purple) associate in the cytoplasm as the large, macromolecular NLRP3 inflammasome in macrophages. Mitochondria are impacted by membrane-bound PRR signals and aid in activating the NLRP3 inflammasome (via Gilkerson R and Materon L, J Clin Immunol Immunother 2014, 1: 004 DOI: 10.24966/CIIT-8844/100004 HSOA Journal of Clinical Immunology and Immunotherapy Review Article AbstractAs the complexity of cellular signaling in inflammatory response emerges, it is increasingly clear that mitochondria are directly involved in, and in some cases are even required for, activation of inflammatory response. As a bioenergetic organellar network, mitochondria dynamically modulate their organization and function in response to cellular signaling cues and metabolic demand. The NLRP3 inflammasome, a caspase-activating multifactor scaffolding assembly, is directly activated by mitochondrial factors and functional parameters. Mit...