Figure 2 Inflammation and ROS. Elevated ROS production as a result of inflammatory signaling can mediate canonical NF-κB activation and downstream inflammatory gene induction, proteasome activity, antioxidant gene transcription, inflammasome activation, and cytokine secretion. The intricate balance between cell death and cell survival is largely modulated by intracellular ROS generation. In general, high intracellular ROS generation causes cell death by activation of cell death pathways (mitochondrial-dependent and -independent), whereas low levels of ROS act as signaling molecules that facilitate cell survival. Death receptors such as TNFR1 cause cell death by inducing high intracellular ROS production. The binding of TNF-α to TNFR1 recruits proteins such as TRADD and TRAF2 to activate TNFR1 signaling. The associated TRADD further recruits FADD and pro-caspase-8, and this whole signaling complex known as DISC is endocytosed, resulting in caspase-8 activation. Similar to TNFR1, the extent of caspase-8 activation determines whether a cell will follow a mitochondrial-dependent pathway or an independent pathway. Low caspase-8 activation follows a mitochondrial-dependent amplification loop which causes Cyt-C release. The released Cyt-C then subsequently binds Apaf-1 and caspase-9 and activates effector caspases such as caspase-3, which causes cell death. In the event of significant caspase-8 activation, it directly activates caspase-3 independent of mitochondria. High intracellular ROS induce sustained JNK activation and causes mitochondrial Cyt-C-dependent cell death. TNFR1 signaling also activates the NF-κB transcription factor by recruiting TRAF-2 and RIPK1 proteins. NF-κB activation is involved in the transcription of anti-apoptotic signaling proteins such as cIAP-2 and Bcl-xL. On the other hand, TNF can activate the NOX1 (neutrophilic) or NOX2 (epithelial) complex. The first step of NOX1/2 activation is the interaction of the cytosolic domain of TNFR1 with RFK and p22phox. The activated NOX complex converts extracellular O2 into O2−•, which extracellular SOD3 then converts into extracellular H2O2. The generated H2O2 passes freely through the plasma membrane and acts as a major source of intracellular ROS. Furthermore, TNF-induced formation of complex II leads to interactions between activated caspase-8, ROMO1 and Bcl-XL in the outer mitochondrial membrane, which reduce mitochondrial membrane potential, triggering MOMP and the production of MtROS. Conversely, if the levels of caspase-8 are high, TNF can activate directly caspase-3 independent of mitochondria, leading to apoptosis. Additionally, Ca2+-activated DUOX produces even more H2O2, which joins the cycle. Another important role of MtROS is the regulation of the inflammasome. MtROS are involved in immune cell activation during inflammation and are primary regulators of NLRP3 inflammasome activation. These high-molecular-weight complexes activate inflammatory caspases (caspase-1 and −11) and cytokines (IL-1β and IL-18). Also illustrated are ROS activating NF-κB directly or indirectly by inhibiting IKK phosphatases, and JNK stimulating mitochondrial ROS production through SAB.
Abbreviations: TNF-α, tumor necrosis factor-alpha; TNFR1, tumor necrosis factor receptor-1; RIPK1, receptor-interacting serine/threonine-protein kinase 1; TRADD, tumor necrosis factor receptor type 1-associated DEATH domain protein; TRAF2, TNF receptor-associated factor 2; cIAP1, cellular inhibitor of apoptosis proteins; Ikβ-α, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha; NF-kβ, nuclear factor kappa-light-chain-enhancer of activated B cells; cFLIP, cellular FLICE inhibitory protein; BclXL, B-cell lymphoma extra-large; SOD, superoxide dismutase; NOX2, NADPH oxidase 2; IL-, interleukin; CXCL, chemokine (C-X-C motif) ligand; FADD, Fas-associated death domain; Casp, Caspase; ROMO1, ROS modulator 1; SAB, SH3 homology associated BTK binding protein; e
−, electron; H
2O
2, hydrogen peroxide; O
2, oxygen; O
2•-,superoxide radicals; ROS, reactive oxygen species; DUOX, dual oxidase; Trx, thioredoxin; TXNIP, thioredoxin-interacting protein; NLRP3, NLR family pyrin domain containing 3; ASC, Apoptosis-associated speck-like protein containing a CARD; JNK, c-Jun N-terminal kinases; ΔΨ, mitochondrial membrane potential; MOMP, mitochondrial outer membrane permeability; Cyt-C, cytochrome C; DIABLO, direct inhibitor of apoptosis-binding protein with low pI; Ca,
Citation2+ calcium ion; Rac, Ras-related C3 botulinum toxin substrate; Noxo1, NADPH oxidase organizer 1; Noxa1, NADPH oxidase activator 1; Fe, iron; RFK, riboflavin kinase.