Juvenile stress leads to long-term immunological metaplasticity-like effects on inflammatory responses in adulthood

Previous studies indicate that individuals exposed to stress in juvenility are more prone to suffer from stress-related psychopathologies in adulthood. Evidence suggests that exposure to enriched environment (EE) conditions alleviates juvenile stress (JVS) effects. Exposure to stress has been found to affect immune responses to challenges, but whether JVS has long-term effects on inflammatory processes remains unclear. Here, we examined the impact of JVS on inflammatory processes in adulthood, and the effects of exposure to EE conditions. Adult rats exposed to JVS showed elevated levels of blood monocytes after induction of peritoneal inflammation. This was associated with higher concentration of blood chemokine ligand type 2 (CCL2), but lower levels of its receptor, chemokine receptor type 2 (CCR2) on these monocytes, indicating reduced ability of these monocytes to be recruited to the inflammatory site. In accordance, JVS led to reduced levels of recruited macrophages at the peritoneal cavity, as well as a reduced activation ratio for the release of peritoneal interleukin-10 (IL-10) by lipopolysaccharide (LPS) activation. EE conditions, which fully reversed the anxiety-like behavior resulting from exposure to JVS, did not reverse JVS-induced alterations in blood concentration of monocytes or peritoneal macrophages, but affected IL-10 activation ratio. This effect was associated with a compensatory elevation of the peritoneal CCL2-CCR2 axis. Our results demonstrate long-term metaplasticity-like effects of JVS, which alter inflammatory processes in response to immune challenges in adulthood. Our results also raise the possibility that EE does not simply reverse the effects of JVS but rather indirectly modulates its impact.