In the last two years, the global pandemic has made us acutely aware of how our bodies respond to viral infection. Within this pandemic, there is another pandemic – a heightened level of stress that is affecting our behaviors, mental health, and potentially our immune systems. The intersection between the immune and stress systems has been extensively studied, but our understanding of how specific stress brain circuits affect discrete elements of the immune system, and how this could impact the body’s ability to respond to various immune challenges, is very limited. A new study by Poller et al.1 published in Nature provides mechanistic insights into how acute stress uses distinct brain circuits to regulate leukocyte dynamics and contribute to differential susceptibility to diseases in response to autoimmune challenges or viral infections.
The idea that stress orchestrates the movement of immune cells to peripheral targets has been previously explored2. While key stress hormones, such as norepinephrine and glucocorticoids, have been implicated in these processes, a direct link between the brain cells that coordinate the neuroendocrine response to stress has remained elusive. Poller et al.1 now provide insights into distinct signaling mechanisms that control the rapid mobilization of neutrophils to circulation, followed by a slow movement of monocytes and lymphocytes from peripheral organs to the bone marrow after acute stress1 (Fig. 1). Consistent with previous work2, the slow transit of monocytes and lymphocytes from peripheral organs to the bone marrow requires the activation of the canonical controllers of the neuroendocrine stress response, the corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVN). These cells release CRH to initiate a cascade of peripheral signals that culminate in an increase in circulating glucocorticoids. Poller et al.1 propose that glucocorticoids act autonomously on leukocytes to enhance the function of the CXC chemokine receptor 4 (CXCR4). CXCR4 has been previously described as a key player in the homing of cells to the bone marrow. This increase in leukocyte sequestration in the bone marrow has opposing effects on how the body responds to an autoimmune challenge versus a viral challenge.
By subjecting acutely stressed and non-stressed mice to experimental autoimmune encephalomyelitis (EAE), Poller et al.1 show that stressed mice have lower clinical severity scores. These effects, which suggest that the mice are protected from disease initiation and progression, require the activation of CRH neurons and the actions of circulating corticosterone. Importantly, they showed that mice lacking CRH are more susceptible to EAE. In summary, acute stress prevents the acquisition of autoimmunity.
The results are quite different when the system is challenged with a virus. Given the context of the pandemic, this is particularly timely, so Poller et al.1 examined the effects of acute stress on viral infections. Compared to age- and sex-matched controls exposed to SARS-CoV-2, stressed mice exposed to SARS-CoV-2 had higher viral titers. These effects also depended on corticosterone. Furthermore, this attenuation of the response to the virus is not specific to SARS-CoV-2, as stress also increases viral titers following exposure to influenza A virus. The main takeaway is that acute stress during the early phase of viral exposure impairs the host’s adaptive immunity against infections.