Ic BAX (34). An example of how c-ABL might be activated is via TGF signaling; in idiopathic pulmonary fibrosis, c-Abl is activated by TGF (35), and silencing of c-Abl inhibits the pro-survival effects of TGF on myofibroblast apoptosis (34). Secondly, in fibrotic tissues, extracellular matrix stiffness is elevated compared to wholesome tissue. This increased stiffness is definitely an essential survival signal for myofibroblasts; through mechanosensing such stiffness final results in intracellular activation of Rho and Rho-associated kinase (ROCK) whose activity increases IL-24 Proteins medchemexpress BCL2-XL expression (36). Importantly, this improved, stiffness-induced, BCL2-XL expression is necessary to counteract the function of the pro-apoptotic protein BIM (36). BIM is an activator of BAX and accumulates in myofibroblasts exposed to a stiff matrix. This accumulation primes the cells to undergo apoptosis (36), and only the continued presence of BCL2-XL prevents this. This balance among BCL-2 and BIM serves a function for the duration of normal wound healing; once the matrix softens for the duration of the final wound remodeling stage, pro-surivival ROCK IL-15 Receptor Proteins Source signaling drops, resulting in loss of BCL-2 expression, and speedy BIMmediated apoptosis of myofibroblasts (36). Recently, it has beenshown that pharmacological inhibition of BCL2-XL can mimic this method and induce targeted BIM-mediated apoptosis in myofibroblasts and in some cases revert established (murine) fibrosis (36). Also, in SSc skin, phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling (37) is enhanced. This pathway facilitates myofibroblasts survival by inhibiting the activity of BAX. It does so by inactivating bcl2associated agonist of cell death (Poor) by way of phosphorylation, following which this protein can no longer inhibit the function of antiapoptotic proteins like BCL2-XL . Several growth elements can induce PI3K/AKT signaling, such as TGF. TGF signaling is improved in skin of SSc patients, and TGF has been demonstrated to induce AKT signaling in dermal fibroblasts to lower myofibroblasts’ sensitivity for Fas-mediated apoptosis (34, 37, 38). Moreover, TGF signaling also lowers expression of acid sphingomyelinase (SMPD1) (39). This enzyme induces the activation of protein phosphatase 2 (PP2A), i.e., an inhibitor of AKT signaling, along with a reduction in SMPD1 thus enhances pro-survival AKT signaling. Additionaly, SMPD1 facilitates Fasdependent apoptosis through its product; i.e., the lipid ceramide, which aids cluster Fas in the cell membrane, therefore facilitatingFrontiers in Immunology www.frontiersin.orgNovember 2018 Volume 9 Articlevan Caam et al.Unraveling SSc Pathophysiology; The Myofibroblastthe formation of death inducing signaling complexes (40). In SSc fibroblasts, it has been shown that TGF lowers Fas-mediated apoptosis and that overexpression of SMPD1 prevented this effect, indicating its significance (39). Lastly, a role for micro RNAs (miRNA) in guarding myofibroblasts against apoptosis has been described in SSc. miRNAs are smaller non coding RNA molecules that will bind messenger RNAs and induce their degradation by way of an RNAinduced silencing complex (RISC). In SSc skin, expression of miRNA21 is increased, and this miRNA targets and degrades pro-apoptotic BAX mRNA (41). Moreover, miRNA21 targets phosphatase and tensin homolog (PTEN), which can be an inhibitor of AKT signaling, as this phosphatase lowers intracellular PIP3 levels, the activator of AKT signaling (38). Via these mechanisms, presence of this miRNA lowers cellul.
