Figure 3

Hypotheses of NALP3 activation via inflammatory pathway. (A1): Alum activates XOR and induces the secretion of uric acid (UA). (A2): Alum-adsorbed antigen (Ag) is internalized by DC via actin-polymerization pathway. (A3): Alum interacts with lipid raft of DC membrane and activates ITAM-Syk pathway to internalize Ag. (A4): Alum-induced production of monosodium urate (MSU) crystals may be internalized by DC in CD16/32-dependent pathway. (B): Alum in phagosome enhances maturation into phagolysosome and release of Al³⁺ and OH⁻. (C): Al³⁺ inhibits the cathepsin L activity and consequently the generated stress induces the rupture of phagolysosomes. (C1): The leaked Ag may bind with MHCI molecule in cytoplasm. (C2): Nanometer-sized Al³⁺ ion precipitates in the cytosol. (C3): The released K⁺ will be exported outside and extracellular adenosine tri-phosphate (ATP) will enter inside via P2X7 molecule. (C4): Cathepsin molecule will be released in the cytosol. (C5): MSU is released in cytosol. (D): Reactive oxygen species (ROS) is generated. The ROS will activate various molecules such as (D1) unknown or (D2) Heat shock protein (HSP)70 that can trigger nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and induces the secretion of IL-1β (D3). (E): Mitochondrion becomes activated and generates ROS (E1) and mitochondrial deoxyribonucleic acid (DNA) (E2). (F): C3, C4, C5, D1, D2, E1, or E2 may activate nucleotide-binding oligomerization domain family-like receptor pyrin domain containing 3 (NALP3) and consequently AC-1 (G). (H): Necrosis-induced release of double stranded (ds)DNA enters cytoplasm and initiates toll-like receptor (TLR)9–interferon regulatory factor (IRF)-3 signaling (I). (J): MSU molecules directly activate myeloid differentiation (MYD)88 signaling. (K): Pro-IL-1β and IL-18 may be transcripted from nucleus. (L): Active caspase (AC)-1 induces the secretion of their matured forms. (M): immunoreceptor tyrosine-based activation motif (ITAM)-Syk-PI3Kδ pathway activates secretion of prostaglandin E2 (PGE2). (N): Alum activates complement.