The Physiopathological Role of IL-33: New Highlights in Bone Biology and a Proposed Role in Periodontal Disease

Figure 1

RANKL-independent signalization pathways of IL-33 and RANKL signaling in circulating monocytes. Binding of IL-33 to its receptor, ST2, leads to recruitment of MyD88 that phosphorylates ERK, activating important factors in the terminal differentiation of osteoclast as TRAF6, NFATc1, and TRAP. Activation of RANK by RANKL induces the recruitment of TRAF6, leading to the phosphorylation of PI3K, p38, and JNK. Upregulation of p62 activates PKC degrading TAB2 by ubiquitin-proteasome complex. PI3K activates AkT that phosphorylate the inhibitory IkB that is degraded by the proteasome, liberating active NFKB. The degradation of TAB2 leads to TAK1 liberation and PKC activation by p62 that, in turn, induce the phosphorylation of NEMO, liberating active NFKB. This molecule translocates to the nucleus inducing gene transcription and contributes to the activation o NFATc1. PI3K and P38 activate AP-1 that translocate to the nucleus forming a complex with NFATc1 to activate osteoclast-specific genes. The RANKL and IL-33 signalization activate intersecting downstream effectors, such as TRAF6, PI3K, JNK, and principally NFKB. Activator protein-1 (AP-1); extracellular signal-regulated kinases (ERK); inhibitor of kB (IKB); interleukin-33 (IL-33); interleukin 1 receptor antagonist (IL1-RA); interleukin-1 receptor-associated kinase 1 (IRAK); IκB kinase (IKK); c-Jun N-terminal kinases (JNK); protein kinase C (PKC); mitogen-activated protein kinases (MAPK); myeloid differentiation primary response gene (MyD); nuclear factor of activated T cells (NFAT); nuclear factor kappa B cells (NFKB); receptor activator of NFKB (RANK); receptor activator of NFKB ligand (RANK-L); TAK-1-binding protein (TAB); TNF receptor associated factors (TRAF); phosphatidylinositol 3-kinases (PI3K); serine/threonine kinase (AKT); regulatory subunit NFKB-essential modulator (NEMO); tartrate-resistant acid phosphatase (TRAP); Toll-interleukin receptor (TIR); transforming growth factor-β activated kinase (TAK); ubiquitin (Ub).