An international study led by Dr. Paolo Fiorina from Boston Children’s Hospital and in collaboration with researchers from University of Milan highlights the beneficial effect of inhibiting the death receptor TMEM219 to restore mucosal healing in inflammatory bowel diseases (IBDs). Fiorina and colleagues demonstrated that the pharmacological blockade of TMEM219 signal through a recombinant protein based on the extracellular portion of the TMEM219 receptor is able to preserve self-renewal ability of intestinal stem cells in IBD, protect intestinal stem cells from cell death induced by TMEM219 activation, and prevent colitis development in mouse models. These results were confirmed by the selective genetic inhibition of TMEM219 on intestinal stem cells LGR5 in vivo which allowed for the preservation of mucosal regeneration and healing in inflammatory bowel disease.
This may thus represent a new mechanism of disease in which TMEM219 overactivation induces intestinal stem cell death and prevents mucosal renewal during inflammation. Previous studies conducted by the same group of researchers had highlighted the importance of the TMEM219 signaling in the context of diabetes, particularly on insulin-producing beta cells. This study goes further and identifies the TMEM219 signals as a novel mechanism of disease in colitis. TMEM219 is also called IGFBP-3R (insulin-like growth factor-binding protein 3 receptor) and IGFBP3 is its natural enodegenous ligand. IGFBP3 has a variety of intracellular ligands that point to its function within major signaling pathways. The discovery of its interaction with the retinoid X receptor has led to the elucidation of roles in regulating the function of several nuclear hormone receptors including retinoic acid receptor-α, Nur77 and vitamin D receptor.
Its interaction with the nuclear hormone receptor peroxisome proliferator-activated receptor-γ is believed to be involved in regulating adipocyte differentiation, which is also modulated by IGFBP-3 through an interaction with TGFβ/Smad signaling. IGFBP-3 can induce apoptosis alone or in conjunction with other agents. On the other hand, IGFBP-3 also has demonstrated roles in survival-related functions, including the repair of DNA double-strand breaks through interaction with the epidermal growth factor receptor and DNA-dependent protein kinase, and the induction of autophagy through interaction with GRP78. The ability of IGFBP-3 to modulate the balance between pro-apoptotic and pro-survival sphingolipids, by regulating sphingosine kinase (SPHK1) and sphingomyelinases (NSMases), may be integral to its role at the crossroads between cell death and survival in response to a variety of stimuli.
Sphingosine and ceramide are two biolipids involved in regulating programmed cell death (apoptosis): the first activates protein kinase C (PKCs) and other proteins involved in cellular defence; ceramide, instead, is an activator of stress kinases (KSR-1, JNK, p38-alpha) which induce the cellular demise. They also work as phosho-forms: sphingosine-1-P is a cellular enhancer of inflammation, vasculogenesis, immune responses and cellular migration; ceramide-1-P, on the contrary, is an anti-apoptotic lipid which may actually stimulate DNA syntesis in various cell types. A phosphoproteomic analysis in intestinal cells cultured in the presence of IGFBP3 demonstrated decreased activation of antiapoptotic factors primarily involved in cell cycle regulation (i.e., IKK-beta and c-Myc), an increased activation of proapoptotic mediators, particularly of eIF4E-BP1, involved in caspase-mediated cell apoptosis.
This might thereby suggest that the TMEM219 signal may also promote cell apoptosis by disrupting cell cycle regulation. Notably, ceramide may induce apoptosis not only by activating kinases or triggering ROS production in mitochondria, but by also regulating caspases activation (e.g. caspase-8 or FLICE). Interestingly, phosphoproteomic analysis also revealed that blocking TMEM219 signaling with the recombinant protein ecto-TMEM219, which prevents IGFBP3 interaction with TMEM219, triggered some positive and prosurvival pathways. Moreover, ecto-TMEM219 abrogated the activation of apoptotic mediators 4E-BP1, c-Btk and NFkb-p65, which further blocked the detrimental effect of TMEM219 and protected intestinal cells from death.
Overall, these results indicate that pharmacological blockade of the IGFBP3/TMEM219 signaling/binding with ecto-TMEM219 or an antagonistic anti-TMEM219 mAb in vivo, ameliorates signs and symptoms of acute colitis and preserves intestinal immune homeostasis. This has broad implication in the treatment of Crohn’s disease and other IBDs, where immune dysregulation and cellular regeneration are tightly intertwined.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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