Immunopsychiatry

Chronic Inflammation: Origins and Mechanisms

For more than 10 years, Fondation FondaMental has been supporting research in immunopsychiatry. Immunologists, epidemiologists, infectious disease specialists, neurobiologists, psychiatrists, and psychologists—working together within national (RTF Immuno-Psychiatry) and international networks (European Network in Immunopsychiatry)—have shown that nearly 40% of people living with mental disorders (depression, bipolar disorders, schizophrenia, autism, etc.) present with persistent low-grade chronic inflammation. This condition results from interactions between environmental risk factors and a genetic vulnerability that limits patients’ ability to cope with stressors such as infections, childhood trauma, air pollution, urban living, and poor lifestyle conditions.

Each of these risk factors triggers a defence response, leading to the production of inflammatory markers in the blood, brain, and gut. The genetic response to these stressors occurs in several stages, all of which have been shown to be impaired in mental disorders. The innate immune response—an immediate reaction—initiates the production of pro-inflammatory cytokines; if insufficient, the body’s defence is weakened. This is followed by mechanisms that should regulate and stop the inflammatory response; if these are also impaired, inflammation persists and becomes chronic. The final stage, the adaptive immune response, further amplifies inflammation and leads to the production of autoantibodies.

Activated Biological Pathways

The persistence of chronic inflammation in turn triggers the activation of several biological pathways that we have begun to characterise. These pathways make it possible to identify more homogeneous clinical subtypes, with known mechanisms that can be specifically targeted with tailored treatments:

Autoimmune psychoses affect approximately 10% to 25% of patients with schizophrenia or bipolar disorders. They are defined by the presence of autoantibodies targeting synaptic receptors, such as anti-NMDA receptor antibodies (Jezequel et al., 2017, Nature Communications) or antibodies against α7 nicotinic receptors (Darrau et al., Translational Psychiatry, 2024). A clinical trial (TIM DEPIST, PI F. Villega, Bordeaux), co-funded by Fondation FondaMental, was launched in October 2024.

Immunometabolism is characterised by the presence of metabolic syndrome, which occurs two to four times more frequently in individuals with mental disorders. It is associated with mitochondrial dysfunction—mitochondria being intracellular organelles responsible for energy production, particularly essential for brain function. Abnormalities affecting all components of mitochondria have been described (for a review, see Bernard et al., Brain, Behavior, and Immunity, 2024; Zachos et al., Psychiatry Research, 2024).

Activation of endogenous retroviruses, which are normally silent viral sequences, can occur in response to viral infections. This reactivation leads to the production of retroviral envelope proteins that are both neurotoxic and neuroinflammatory (Tamouza et al., Translational Psychiatry, 2023).

Alterations in the gut–brain axis are also triggered by chronic inflammation, leading to increased intestinal permeability and changes in the gut microbiota (dysbiosis). Dysbiosis associated with autism has been described, along with links to genes involved in intestinal diseases (Dectin). A clinical trial (MOODSWING) has been initiated in treatment-resistant depression, using polymicrobiotherapy, whose efficacy had previously been demonstrated in animal models (Faucher et al.).

Acceleration of ageing processes has been demonstrated through telomere shortening—telomeres being structures at the ends of chromosomes that protect their stability (Spano et al., 2022)—as well as epigenetic alterations reflecting genetic modifications (Bourdon et al., Psychiatry Research, 2023), and the ageing of T lymphocytes following viral infections and childhood trauma (Foiselle et al., Brain, Behavior, and Immunity, 2022).

Activation of the kynurenine pathway, triggered by cytokines, leads to reduced serotonin synthesis and increased production of neurotoxic markers such as glutamate (Skorobogatov et al., Brain, Behavior, and Immunity, 2024).

Several Therapeutic Trials Conducted

In 2024, the DEPIL study was published. This double-blind clinical trial evaluated the efficacy of low doses of cytokines (IL-2), which stimulated the production of regulatory T cells and led to an improvement in bipolar depression (Leboyer et al., 2024).

Scientific Publications in Immunopsychiatry