Chronic Stress & IL-10/STAT3
A study published in Brain, Behavior, and Immunity journal indicates that the interleukin (IL)-10/STAT3 pathway may play a key role in the immunosuppression induced by chronic stress.
IL-10 is a major anti-inflammatory cytokine, which possesses potent immunosuppressive actions. Stress mediators, particularly catecholamines (CAs), are potent IL-10 inducers, and in clinical conditions such as brain trauma, the massive CAs-induced IL-10 release has been linked to severe immunosuppression (IJ Elenkov et al., Proc Assoc Am Physicians, 1996, 108:374; F Ramírez F et al., J Immunol, 1996, 156:2406; C Woiciechowsky et al., Nat Med, 1998, 4:808). It is also known that STAT3, a key member of the Stat family, can be activated by IL-10 signaling, and IL-10R appears unique in promoting a potent anti-inflammatory response via STAT3 induction (El Kasmi et al., J Immunol, 2006, 177:7880).
In this study, Dan Hu and colleagues from the East Tennessee State University, Johnson City, TN, US and the Wuhan University, Wuhan, China measured serum IL-10 levels, IL-10 production by splenocytes, and activation of splenic STAT3 in mice that have been subjected to chronic physical restraint stress.
The authors demonstrated that the IL-10/STAT3 axis is activated by the TLR4/p38 pathway following chronic stress. Furthermore, evidence was obtained that the IL-10/STAT3 pathway may also be involved in triggering lymphocyte apoptosis, the suppression of IL-12 production, and the induction of a T helper (Th)2 shift.
The study provides new insights into the mechanisms driving stress-induced immunosuppression and may suggest new therapeutic strategies along these lines.
Source: Brain Behav Immun. 2014, 36:118.
Read more: sciencedirect.com
Updates
A 2018 study investigated neuro-inflammation in the hippocampus of rats after exposure to chronic mild stress (CMS), and microglial activation and hippocampal neuro-inflammation were detected by using a combinatory approach of in vivo.
The results show that 12 weeks of chronic mild stress induced remarkable depressive- and anxiety-like behavior, simultaneously causing hippocampal microglial activation and activation of NLRP3 inflammasome. This was linked to upregulation of inflammatory mediators, such as interleukin-1β (IL-1β), IL-6, and IL-18 in the hippocampus after exposure to chronic stress. Of note, the anti-inflammatory mediators, such as IL-4 and IL-10, were also increased in the hippocampus following chronic mild stress. The authors of this study suggest that their data indicate that microglial activation mediates the chronic mild stress-induced depressive- and anxiety-like behavior and hippocampal neuro-inflammation.
A 2020 study investigated the effect of chronic movement restraint with variable duration and assessed in several physiological and behavioral readouts known to reflect chronic stress states. Thus, body weight, levels of plasma corticosterone, hippocampal pro-and anti-inflammatory cytokines, anxiety-like (novelty suppressed feeding and elevated plus maze) and motivated behaviors (sucrose negative contrast test and forced swim test) were evaluated three days after the end of the chronic protocol.
The study reports that chronic stress induced by movement restraint of variable duration reduced body weight gain, increased hippocampal cytokine levels, and altered motivated behaviors.
It has been suggested that inflammation can be a link between stress and depression. The authors of this study found significantly higher levels of pro-inflammatory cytokines, as well as the anti-inflammatory cytokine IL-10, in the hippocampus of Chronic Unpredictable Movement Restraint (CUMR) animals.
These results are in line with the above-discussed 2018 study reporting the induction of depressive-like behavior, microglial activation and increased hippocampal levels of both pro- (IL-1β, IL-6 and IL-18) and anti-inflammatory (IL-4 and IL-10) cytokines after 12 weeks of chronic unpredictable stress.
The authors suggest that this chronic stress model leads to a general recruitment of microglia cells, which are responsive to various different stressors, including chronic restraint.
A 2021 study indicates that long-term stress abrogates both T helper 1 (TH1)- and TH2-type responses orchestrated by invariant natural killer T (iNKT) cells. Activated iNKT cells in stressed mice exhibit a “split” inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23 and IL-27 spikes.
The authors found that stress compromises the ability of iNKT cells to trigger TH1- and TH2-type responses and to promote antimetastatic immune surveillance, and that, mechanistically, this hyporesponsive state is dependent upon direct GR signaling in iNKT cells, which remain uniquely and remarkably recalcitrant to glucocorticoid-inflicted apoptosis.
These authors also discuss that stress generates a mixed inflammatory signature and also skews iNKT cell responses in favor of select anti-inflammatory cytokines, namely IL-10 and IL-27, but not TGF-β. As per these authors, to what extent these immunosuppressive cytokines inhibit TH1 and/or TH2 immunity following iNKT cell stimulation remains to be determined.
