Transient receptor potential vanilloid 1 activation induces autophagy in thymocytes through ROS-regulated AMPK and Atg4C pathways

Abstract

Autophagy is a highly conserved process involved in lymphocyte development and differentiation. Herein, we demonstrated for the first time that triggering of TRPV1 by the specific agonist CPS induces autophagy in mouse thymocytes. TRPV1-dependent autophagy required [Ca(2+)](i) and ROS generation, resulting in AMPK activation. CPS specifically increased Atg4C mRNA expression and induced oxidation of Atg4C protein by ROS generation. TRPV1-triggered autophagy was Atg6/Beclin-1-dependent, as demonstrated by the use of Beclin-1(+/-) transgenic mice, and involved ROS- and AMPK-mediated up-regulation of Beclin-1 expression. Autophagy is activated as a prosurvival process, as its inhibition triggered apoptosis of thymocytes: this effect was accompanied by down-regulation of Atg4C, Bcl-X(L), and Irgm1 mRNA expression, decreased Bcl-X(L) and Beclin-1 protein levels, and caspase-3 activation, suggesting the existence of a molecular interplay between autophagic and apoptotic programs. TRPV1 activation by CPS altered the expression of CD4 and CD8α antigens, inducing the development of DP(dull). Interestingly, we found that CPS induces autophagy of DP(dull) cells, and inhibition of CPS-induced autophagy by the 3-MA autophagic inhibitor induces apoptosis of DP(dull) cells, suggesting the presence of an interplay between autophagic survival and apoptotic cell death. Overall, our findings suggest that DP(dull) cells constitute a distinct thymocyte subpopulation involved in the homeostatic control of cellularity and in the responses to chemical stress signals during thymocyte maturation, via regulating autophagy and apoptosis in a TRPV1-dependent manner.

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

“…For example, stimulating TLR4 with lipopolysaccharide could induce autophagosomes [33]. Defective autophagy would decrease the number of naive T cells [34] and B cells [35] and facilitate CD4 + T-cell apoptosis after activation [36]. However, few studies have examined whether regulating MSC autophagy would change the immunosuppressive capacity of these cells.…”

Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus

“…Additionally, AMPK-dependent autophagy has been observed in the TRPV1-mediated inhibition of vascular smooth muscle foam cell formation [17]. Similar pathways for the induction of autophagy by TRPV1 and AMPK have been shown in thymocytes [39]. In our present study, autophagy deficiency and reduced TRPV1 expression were observed in diabetic mice, as indicated by decreased numbers of autophagolysosomes and the expression of LC3II and LAMP2.…”

Transient receptor potential vanilloid 1 is expressed in human cytotrophoblasts: Induction of cell apoptosis and impairment of syncytialization

“…TRPV1 is sensitive to several stimuli such as noxious, heat, low pH and several endogenous and exogenous molecules (Vriens et al, 2009). It is mainly involved in temperature sensing and nociception, but TRPV1 also participates in other cellular processes such as apoptosis (Contassot et al, 2004;Pan et al, 2013;Song et al, 2013), muscle contraction (Charrua et al, 2007;Matsumoto et al, 2009;Shimizu et al, 2007), autophagy (Farfariello et al, 2012;Li et al, 2014) and inflammation (Fernandes et al, 2012;Trevisani et al, 2004;Vigna et al, 2011). Some of the endogenous ligands of TRPV1, the endovanilloids, are the endocannabinoids anandamide (AEA) and N-arachidonoyldopamine (NADA), the oleoylethanolamide (OEA), protons, prostaglandins and lipoxygenase (LOX) or cytochrome P450 (CYP450) products (Vriens et al, 2009).…”