title: Chronic stress promotes lymphocyte reduction through TLR2 mediated PI3K signaling in a β-arrestin 2 dependent manner.
abstract: Physical and psychological stress can alter the immune system in both humans and animals. Stress is a known risk factor for numerous human diseases, such as infectious and autoimmune diseases, and cancer. Toll-like receptors (TLRs) play a pivotal role in the induction of innate and adaptive immune response. Our previous studies have shown that TLR4 deficiency prevents stress-induced splenocyte reduction. However, the role of TLR2 in stress-mediated lymphocyte reduction is unknown. In this study, we investigated the effects of TLR2 ligands on stress-induced lymphocyte reduction. We also defined whether the phosphoinositide 3-kinases (PI3Ks)/Akt pathway contributes to TLR2-mediated lymphocyte numbers altered by stress. Our data have shown that stimulation of TLR2 by TLR2 ligands peptidoglycan (PGN) or Pam3CSK4 (Pam3) attenuates stress-induced reduction in lymphocyte numbers. However, TLR2 ligand-induced protection from stress-induced lymphocyte reduction is lost in TLR2 deficiency in mice. Furthermore, stimulation of TLR2 by PGN induces protection from stress-induced reduction in the number of splenocytes through PI3K. Moreover, PGN dramatically increases the level of phosphorylation of Akt through a PI3K-dependent manner. Moreover, we found that stimulation of TLR2 by PGN induced protection from stress-induced reduction in splenocyte numbers is abolished in β-arrestin 2 deficient mice. In addition, PGN-induced immune protection in stress-induced changes of cytokine levels appears to require β-arrestin 2, a multifunctional adaptor and signal transducer. Collectively, our study thus demonstrates that stimulation of TLR2-mediated PI3K signaling attenuates splenocyte reduction induced by stress, and that β-arrestin 2 modulates TLR2-mediated immune response following stress.
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States. helikezai@yahoo.com
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gene
authors.initials: G
authors.lastname: Lesage
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Gregory
authors.initials: G
authors.lastname: Hanley
authors.forename: Shenggang
authors.initials: S
authors.lastname: Sun
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D016131:Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013315:Stress, Psychological / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019869:Phosphatidylinositol 3-Kinases