Repeated Stress Exaggerates Lipopolysaccharide-InducedInflammatory Response in the Rat Spleen

Abstract Spleen is an immune organ innervated withsympathetic nerves which together with adrenomedullarysystem control splenic immune functions. However, themechanism by which prior stress exposure modulates theimmune response induced by immunogenic challenge isnot sufficiently clarified. Thus, the aim of this study was toinvestigate the effect of a single (2 h) and repeated (2 hdaily for 7 days) immobilization stress (IMO) on the innateimmune response in the spleen induced by lipopolysaccharide(LPS, 100 lg/kg). LPS elevated splenic levels ofnorepinephrine and epinephrine, while prior IMO preventedthis response. LPS did not alter de novo productionof catecholamines, however, prior IMO attenuated phenylethanolamineN-methyltransferase gene expression. Particularlyrepeated IMO exacerbated LPS-induced downregulationof a1B- and b1-adrenergic receptors (ARs),while enhanced a2A- and b2-AR mRNAs. Elevatedexpression of inflammatory mediators (iNOS2, IL-1b, IL-6,TNF-a, IL-10) was observed following LPS and repeatedIMO again potentiated this effect. These changes wereassociated with enhanced Ly6C gene expression, a monocytemarker, and elevated MCP-1, GM-CSF, and CXCL1mRNAs suggesting an increased recruitment of monocytesand neutrophils into the spleen. Additionally, we observedincreased Bax/Bcl-1 mRNA ratio together with reduced Bcell numbers in rats exposed to repeated IMO and treatedwith LPS but not in acutely stressed rats. Altogether, thesedata indicate that repeated stress via changes in CA levelsand specific a- and b-AR subtypes exaggerates theinflammatory response likely by recruiting peripheralmonocytes and neutrophils to the spleen, resulting in theinduction of apoptosis within this tissue, particularly in Bcells. These changes may alter the splenic immune functionswith potentially pathological consequences.Keywords Spleen Stress Lipopolysaccharide Adrenergic receptors Cytokines Immune cells Inflammatio