Decreasing Pro-Inflammatory Signalling as an Antidepressant Strategy in Pre-Clinical Models of Major Depressive Disorder

Author: Antonio Inserra

Inserra, Antonio, 2018 Decreasing Pro-Inflammatory Signalling as an Antidepressant Strategy in Pre-Clinical Models of Major Depressive Disorder, Flinders University, College of Medicine and Public Health

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Mounting evidence suggests an involvement of neuroinflammation in major depressive disorder (MDD). Psychological stress activates pro-inflammatory signalling by means of Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome assembly and processing of pro-inflammatory cytokines, which exacerbate depressive-like symptoms.

To test the antidepressant efficacy of inhibiting pro-inflammatory signalling during stress exposure we used caspase 1 (Casp1) knockout (-/-) mice and mice simultaneously lacking Casp1, inducible nitric oxide synthase (Nos2) and interferon gamma receptor (Ifngr) genes in pre-clinical MDD paradigms. We assessed: a) baseline behaviour, b) the behavioural response to chronic stress, c) the levels of the circulating adrenocorticotropic hormone (ACTH) and corticosterone (CORT) following stress, in (Casp1, Ifngr, Nos2)-/- triple knockout mice, and d) gut microbiome composition in response to chronic stress and pharmacological CASP1 inhibition with minocycline.

We found that Casp1-/- mice and (Casp1, Ifngr, Nos2)-/- mice display decreased anxiety- and depressive-like behaviour. These two mouse strains also have increased locomotor activity and Casp1-/- mice has increased locomotor skills. Similarly, CASP1 inhibition with minocycline ameliorated stress-induced depressive-like behaviour in wild-type (wt) mice and shifted gut microbiota composition compared to stress treatment alone. We observed shifts in gut microbiome composition following stress with increased representation of bacterial species conducive to a pro-inflammatory environment, which were decreased following pharmacological CASP1 inhibition. Moreover, we observed that CASP1 inhibition affects the response to chronic stress by preventing the exacerbation of depressive- and anxiety-like behaviours. Lastly, we found that (Casp1, Ifngr, Nos2)-/-mice display a decreased exacerbation of anhedonic-like behaviour after stress compared to wt mice. Interestingly, no differences were found in the level of circulating CORT and ACTH between (Casp1, Ifngr, Nos2)-/- and wt mice.

Together, these results point towards antidepressant-like effects of pro-inflammatory signalling inhibition in MDD, and suggest that at least some of these effects are mediated by changes in gut microbiome composition. Based on our findings and corroborated by the increasing evidence connecting psychological stress, immune activation, gut dysbiosis and co-morbid illnesses, we formulate the “microbiome-inflammasome” hypothesis of major depression and co-morbid systemic illnesses. This hypothesis speculates that NLRP3-orchestrated processes represent a key node in a) stress-induced gut dysbiosis, b) dysbiosis-induced inflammatory dysregulation which lead to depressive symptoms, c) dysbiosis-induced dysregulation of neurotransmitter production, which exacerbates depressive symptoms, d) dysbiosis-induced immune activation, which leads to the development of co-morbid systemic conditions, and e) immune dysregulation resulting from systemic conditions leading to MDD and dysbiosis.

Future studies should aim at streamlining diagnostic strategies to identify MDD patients with dysregulated immune profiles, who could benefit from anti-inflammatory therapies. Finally, the clinical safety and efficacy of direct inhibition of pro-inflammatory pathways as well as their indirect inhibition by means of psychobiotics administration, faecal microbiota transplantation and diet should be further investigated in MDD patients. This could lead to the identification of novel, more efficacious, personalized therapeutic strategies in MDD.

Keywords: Inflammation, Major Depressive Disorder, MDD, Cytokines, Gut Microbiome, Caspase 1, NLRP3 inflammasome, Interferon Gamma, Nitric Oxide Synthase, Chronis stress, Chronic Unpredictable Mild Stress, Chronic Restraint Stress, Minocycline, Microbiome-Inflammasome Hypothesis of Major Depression, Inflammasome Signaling, Neuroinflammation, Neuroimmunomodulation, Stress Hormones, Anhedonic-like Behaviour, Depressive-Like Behaviour, Anxiety-Like Behaviour.

Subject: Psychiatry thesis

Thesis type: Doctor of Philosophy
Completed: 2018
School: College of Medicine and Public Health
Supervisor: Julio Licinio