In a review published in Nature Reviews Rheumatology, researchers discussed the interactions between central and peripheral immunobiological mechanisms associated with rheumatoid arthritis (RA) and major depressive disorder (MDD).
They further described the role of inflammatory proteins, the effect of peripheral inflammation on various parts of the brain, and the relationship between alterations in the brain and inflammation-driven depression.
Study: Immune mechanisms of depression in rheumatoid arthritis. Image Credit: pikselstock/Shutterstock.com
RA is a chronic autoimmune inflammatory disease that negatively affects synovial joints and multiple other organs. Depression is a common, clinically heterogeneous condition affecting every other patient with RA. Increasing evidence suggests that RA and depression have overlapping features and may be modulated by each other.
Data suggest that depression is a risk factor for RA, and patients diagnosed with RA early in life are more susceptible to depression. Additionally, RA patients with depression are observed to show functional progression as well as a reduced response to treatment, leading to poor outcomes. However, the precise biological mechanisms underlying this association are not clearly understood.
Therefore, this review focuses on understanding the link between these two conditions and the underlying mechanisms while exploring the interplay between the nervous and immune systems in RA patients.
Shared cytokines in RA and depression
Pro-inflammatory cytokines that are amplified in RA are also known to be causally associated with depression. Various cytokines are implicated in RA and depression, including interleukin (IL)-16, IL-18, IL-1, IL-6, and tumor necrosis factor (TNF).
Peripheral immune signals to the brain
The peripheral immune signals the brain via two known routes: neural and humoral. In the neural route, molecules that mediate inflammation can bind and activate receptors on sensory neurons, including those in the dorsal root ganglia (DRG) and the vagus nerve.
The activated sensory neurons then relay the signal back to the cerebral cortex of the brain via the spinal cord. The signal is then transmitted to higher brain centers, which modulates the immune system locally and systemically.
In the humoral route, immune cells release molecules capable of crossing the blood-brain barrier (BBB) and influencing brain cells or activating the endothelial cells of BBB.
As observed in experimental studies conducted in mice, this pathway leads to the release of chemokines that are involved in neuronal plasticity, resulting in depression-like behavior and cognitive impairment.
Immune responses in the brain
In the brain, existing neural cells and recruited immune cells release several inflammatory proteins that aid neuroimmune communication. When cytokines and chemokines are released by neurons, microglia, astrocytes, peripheral immune cells, and endothelial cells, they influence neurological and immunological processes.
For example, during inflammation, the recruitment of peripheral monocytes to the brain is associated with dendrite remodeling and cognitive impairment, potentially leading to depression. Chronic peripheral inflammation in RA induces local microglial activation within the brain, leading to altered microglial expression.
Although microglia are commonly linked to inflammatory changes in the brain, recent studies indicate a more complex role for microglia in neurological health.
Contrary to earlier belief, as per studies in mice, microglia found in the brain are not only derived from peripheral blood but also from meninges and the bone marrow in the skull. However, there’s a shortage of studies exploring this aspect in humans.
Astrocytes also play a role in brain inflammation. The activation of astrocytes by cytokines from microglia is shown to result in the release of neurotoxic factors that impact neuronal health and behavior.
Mechanisms that link depression and inflammation
Immune-related inflammation is implicated in the pathophysiology of depression. Various pathways are triggered in RA, which may lead to inflammation-related behaviors.
These pathways include inflammasome activation, the kynurenine pathway, neuroplasticity, and the pathways of the glutamatergic and serotonergic systems.
Brain regional variation
Although regional changes within the brain and the underlying mechanisms continue to be studied mostly using animal models, neuroimaging studies in humans have greatly improved our understanding of inflammation-related changes in the brain.
Advances in magnetic resonance imaging (MRI) have provided insights into the role of inflammation in depression beyond traditional structural assessments and histology-based studies. Emerging evidence suggests that the brain regions affected by inflammation and depression are the striatum, the hippocampus, the amygdala, and the insula.
The present review article provides a comprehensive overview of the link between immune mechanisms and depression in patients with rheumatoid arthritis. It emphasizes the need for further research in this field.
Furthermore, clinical trial data suggest that immune modulation may be a promising approach for the treatment of comorbid depression in patients with rheumatoid arthritis, thus potentially reducing the global burden of this debilitating condition.