Figure 1: Targets and action of therapeutic agents in Familial Mediterranean fever (FMF). A central role in innate immunity is played by the inflammasomes, a group of multi protein cytoplasmic complexes. Among different inflammasomes, the NALP3 inflammasome is the best investigated and the different components comprise NALP3, ASC, CARDINAL, and caspase 1 [154]. A) Putative events likely involved in the formation of NALP3 inflammasome [155]. Under the action of exogenous and host ligands (e.g., ATP, bacterial messenger RNA, uric acid crystals, low intracellular potassium, skin irritants, muramyl dipeptide), the inflammasome is activated (first event: NALP3 oligomerization) followed by recruitment of ASC via PYD domain and caspase 1 via homotypic CARD interaction of ASC. A second molecule of procaspase-1 is recruited via the interaction of CARDINAL with NAPL3 (FIIND-NAD domains, respectively and by the CARDINAL CARD domain vs. procaspase-1). This key steps trigger the activation of caspase-1 from its precursor procaspase-1, and ultimately to the generation of active IL-1β from its inactive precursor pro-IL-1β [33]. Inflammasome activity is normally dampened down by some cytoplasmic proteins, including pyrin [39,78], which is expressed in the cytoplasm of neutrophils, eosinophils, dendritic cells, mature monocytes, serosal and synovial fibroblasts, and cells derived from the colon and prostate cancer (see text). In FMF, the mutated MEFV gene encoding pyrin is associated with abnormal NALP3 inflammasome pathway [38,39]. Alternative, slightly different pathways of inflammasome assembly leading to IL-1β cannot be excluded [39]. B) Formation of NALP3 inflammasome with respect to therapeutic agents showing efficacy in FMF. (a) Pyrin in FMF is genetically mutated and is unable to inhibit the C5a activation promoted by the activated caspase-1. The consequence is the onset of a full-blown inflammation. The biology of interleukin (IL)-1 is shown, starting in the cell nucleus from DNA pathway. Steps include intracellular processing of pro-IL-1β into active IL-1β. This step is triggered by the inflammasome. (b) IL-1β binds the ligand-binding chain IL-1RI, and this step is followed by recruitment of a co-receptor chain accessory protein IL-1RAcP. At this stage, the two anti-IL-1β agents rilonacept and canakinumab are effective. Both bind IL-1β and block its binding to the receptors. (c) Anakinra is the homolog of the human IL-1 receptor antagonist (rhIL-1Ra) and acts as competitive inhibitor of IL-1 activation. Rilonacept, canakinumab, and anakinra reduce or block the IL-1β dependent inflammation. (d) Etanercept acts as anti-TNF-α agent by binding the TNF-α (tumor necrosis factor-α). The TNF receptor (TNFR) is unable to induce the inflammasome. (e) Colchicine (IUPAC Name: N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5Hbenzo[a]heptalen-7-yl] acetamide; Molecular Formula: C22H25NO6; Molecular Weight:399.437) acts on Tubulin-α and -β (high-affinity binding site) and binds irreversibly tubulin. This step prevents the dockage of tubulin into the (+) ends of microtubules. There is structural imbalance or instability of microtubules in maintaining cell structure, in cell division (mitosis and meiosis)-including the formation of mitotic spindles, and in motion. Colchicine inhibits acute phase reactants and NALP3 and blocks the induction of inflammasome. Abbreviations: - ASC- apoptosis-associated speck-like protein containing a CARD - CARD- caspase-recruitment domain - FIIND- domain with function to find - IL- interleukin - LRR- leucine-rich repeat - NACHT- domain present in NAIP (neuronal apoptosis inhibitor protein), major histocompatibility complex class II transactivator, HET-E (incompatibility locus protein from Podospora anserina) and telomerase-associated protein - NAD- NACHTassociated domain - NALP3- NACHT domain, LRR domain, and pyrin domain-containing protein - PYD- pyrin domain Adapted from Grattagliano et al. Novel Therapeutics for the Treatment of Familial Mediterranean Fever: from colchicine to biologics. Clin Pharmacol Ther. 2013 [2].