Effects Of Psychological Stress On MDSC And Endotoxin Shock And The Underlying Mechanisms

Psychological stress has been proven an important factor in influencinghuman health. More and more studies have suggested a close association betweenpsychological health and physical health. Up to30percent of diseases are causedby psychological disorder, and about200kinds of diseases was associated withemotion. A psychological stress response is short lasting and adaptive processesoccur very rapidly. However, if individuals are repeated stressed, neuroendocrinedysregulation can be prolonged and adversely affect critical functions such asimmune surveillance, gastrointestinal integrity, bacterial clearance, virus defenseand wound healing. As a result it is important to study the effects of psychologicalstress on immune system and cells. Myeloid-derived suppressor cells (MDSC) areheterogeneous populations including immature macrophages, neutrophils, anddendritic cells. MDSC were initially found in mouse tumor model and cancerpatients. Now many studies have revealed the association between MDSC andtumor onset as well as metastasis, which suggest an important role of MDSC inimmune system. Whether or not psychological stress might alter the quantity andquality of MDSC is one important topic we will study.In present work, we established the restraint stress model, apply multipletechnology such as ELISA,FACS and Western Blot to investigate effect ofpsychological stress on MDSC. We found that mice subjected to5days' restraintstress exhibited smaller spleens,decreased splenocytes and Peripheral blood (PB)cells. However chronic stress led to a marked expansion of MDSC in the bonemarrow, as well as their mobilization to the peripheral blood and accumulation inthe spleens. Depending on the intensity of Gr-1, MDSC were divided into towsubpopulations: CD11b~+Gr-1highMDSC with marginal immunosuppressive ability and CD11b~+Gr-1intMDSC with overt immunosuppression. Here, we found thatchronic psychological stress increased both CD11b~+Gr-1hiand CD11b~+Gr-1intsubpopulations, while acute stress specifically increased the CD11b~+Gr-1hisubpopulation in the peripheral blood as well as in the spleens. The effect andmechanism of MDSC on aquired immunity have been widely proven, yet theassociation between MDSC and natural immune system has not been fullyunderstood. Data from coculture of macrophages with MDSC revealed that MDSCcould inhibite both the inflammatory cytokine production and phagocytosis ofmacrophages. Moreover MDSC inhibited the inflammatory cytokine production ofmacrophages via a contact-dependent manner.Chronic psychological stress is associated with persistent activation of thehypothalamic-pituitary-adrenal (HPA) axis, which leads to continuously elevatedlevels of stress hormones such as glucocorticoid and catecholamines. We foundthat blockade of both β-adrenal receptor and glucocorticoid receptor did not affectthe psychological stress-induced MDSC expansion,which indicated that singlestress hormone might not be able to induce MDSC expansion in vivo.To further investigate the effect of psychological stress on natural immuneresponse, we established murine endotoxin shock model. Endotoxin shock is oneof the most dangerous diseases in ICU with up to30percent lethality. LPS is themost important factor contributing to this disease. Macrophages and neutrophilsare main target cells of LPS. Catecholamine is one of the most important hormonein psychological stress. Injection of catecholamine could mimick a similarresponse with stress in mouse. Thus we used isoproterenol to study the effects ofpsychological stress on endotoxin shock.Isoproterenol was a β-adrenoceptor agonist, could elevate the intracellularCyclic Adenosine monophosphate (cAMP) level which led to a decreasedinflammatory cytokine production. Clinically it was commonly used in therapingheart failure and asthma. In present work we found that isoproterenol could increase the lethality of either LPS-or E.coli-induced shock, aggravate liver injure,while a more powerful cAMP agonist cholera toxin exibited a protective effectfrom endotoxin shock. It has been certified that over-production of inflammatorycytokines such as TNF-α and liver injure play vital roles in endotoxin shock. Wedemonstrated that isoproterenol could increase serum TNF-α level, as well as thesusceptibility of hepatocytes to TNF-α-induced apoptosis. Investigation of cAMPand downstream transcription factor c-fos confirmed that isoproterenol couldelevate cAMP and c-fos level which indicated an cAMP-independent manner.CD14and TLR-4are two binding receptors of LPS which trigger the immuneresponse. Thus we measured CD14and TLR-4density of peripheral bloodleukocytes (PBL), and found that isoproterenol increased specifically CD14expression in PBL. Further experiments demonstrated that isoproterenol couldincreased both CD14expression and TNF-α production of neutrophils.In conclusion, our studies demonstrated the effects and possible mechanismsof psychological stress on MDSC. Psychological stress could induce MDSCexpansion; acute and chronic psychological stress could induce differentsubpopulations of MDSC which may explain the different role on immune system;as MDSC promoted cancer onset and progression, our work provide evidence onchronic psychological stress inducing cancer onset; as MDSC inhibitedmacrophages function, we provide evidence on the negative effect of chronicpsychological stress on bacterial clearance. In addition, we found thatisoproterenol aggravate endotoxin shock via increasing CD14expression andTNF-α production of neutrophils which provide evidence of side effects ofisoproterenol and importance of psychological therapy in endotoxin shock patients;we also found that CTX could protect mice from lethal endotoxin shock whichmay become an target in shock therapy.