Low-Level Stress Induces Production of Neuroprotective Factors in Wild-Type but Not BDNF^+/-Mice: Interleukin-10 and Kynurenic Acid

Abstract

Background:Brain-derived neurotrophic factor (BDNF) deficiency confers vulnerability to stress, but the mechanisms are unclear. BDNF+/- mice exhibit behavioral, physiological, and neurochemical changes following low-level stress that are hallmarks of major depression. After immune challenge, neuroinflammation-induced changes in tryptophan metabolism along the kynurenine pathway mediate depressive-like behaviors.Methods:We hypothesized that BDNF+/- mice would be more susceptible to stress-induced neuroinflammation and kynurenine metabolism, so BDNF+/- or wild-type littermate mice were subject to repeated unpredictable mild stress. Proinflammatory cytokine expression and kynurenine metabolites were measured.Results:Unpredictable mild stress did not induce neuroinflammation. However, only wild-type mice produced the neuroprotective factors interleukin-10 and kynurenic acid in response to repeated unpredictable mild stress. In BDNF+/- mice, kynurenine was metabolized preferentially to the neurotoxic intermediate 3-hydroxykynurenine following repeated unpredictable mild stress.Conclusions:Our data suggest that BDNF may modulate kynurenine pathway metabolism during stress and provide a novel molecular mechanism of vulnerability and resilience to the development of stress-precipitated psychiatric disorders.

The role of cytokines in the pathophysiology of suicidal behavior

“…Other changes in resiliency systems may also confer vulnerability to disease. Following mild stress, BDNF +/- mice did not increase production of the anti-inflammatory cytokine IL-10 or of the neuroprotective branch of the kynurenine pathway, contrary to wild-type mice (Dugan et al, 2015). More studies are needed to clarify these less investigated pathways.…”

Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice

“…6 ). Both acute and chronic stress increase brain KynA ( Dugan et al., 2016 , Pawlak et al., 2000 ) despite unchanging Kat2 expression ( Fig. 7 ).…”

“…Thus, our data highlight a significant perturbation of Ido2 and Tdo2 regulation within the brain of Ido1 KO mice. The specific role for astrocytes in acute stress is supported by reports of stress-induced increases in central kynurenic acid (KynA) ( Dugan et al., 2016 , Kiank et al., 2010 , Pawlak et al., 2000 ), the major downstream Kynurenine Pathway product produced by astrocytes ( Guidetti et al., 2007 , Kiss et al., 2003 , Zmarowski et al., 2009 ). Future studies examining the effect of stress on the Kynurenine Pathway should consider the role of all three DOs and examine cell-specific changes.…”

“…Most notably, astrocytes are enzymatically equipped to produce kynurenic acid (KynA) a glutamate (NMDA) and acetylcholine (α 7 nACh) receptor antagonist ( Guillemin et al., 2001 , Wu et al., 2010 ), while microglia produce quinolinic acid (QuinA) and 3-hydroxykynurenine (3-HK) which are NMDA receptor agonists ( Guillemin et al., 2004 , Heyes et al., 1996 ). A recent study found that chronic unpredictable stress increased central Ido1 and Tdo2 mRNA coincident with increased KynA concentrations, but unchanged 3-HK ( Dugan et al., 2016 ). This would suggest a specific role for astrocytes in stress-induced DO induction.…”

Interplay of Brain-Derived Neurotrophic Factor and Cytokines in Schizophrenia

“…In study of Lin et al (2016) has been shown that application of BDNF in human Schwann cells increased the secretion of IL-6 through the Janus kinase-signal transducer and activator of transcription pathway activation (38), crucial for the development and function of the immune system (39). Also, wild type mice (BDNF +/+ ) display higher IL-10 secretion in response to low-level stress compared to BDNF-deficient mice (40).…”