Here we suggest a new hypothesis for depression and comorbid illnesses based on evidence of bidirectional pathways between psychological stress and systemic diseases, and danger substances and depression (Fig. 4). As previously discussed, psychological stress can activate the NLRP3 inflammasome, leading to the release of IL-1β, which can contribute to the pathophysiology of systemic illnesses such as diabetes, cardiovascular, and inflammatory diseases. In addition, danger substances such as fatty acids and allergens can activate the NLRP3 inflammasome and thereby elevate IL-1β and contribute to depression symptoms. Based on this hypothesis, depressed patients may be more susceptible to NLRP3-associated diseases. In parallel, patients with NLRP3-associated systemic diseases are more likely to show depressive symptoms. These two pathways can also work in conjunction: for example, in diabetes and cardiovascular disease, psychological stress, along with fatty acids and cholesterol crystals, could act together to hyper-activate the NLRP3 inflammasome, and thereby increase the susceptibility to depression via elevated release of IL-1β.
