For the past two years, the global pandemic has made us extremely aware of how our bodies respond to viral infection. Within this pandemic is another pandemic — a level of heightened stress that is affecting our behaviors, mental health and potentially our immune systems. The intersection between immune and stress systems has been studied extensively, but our understanding of how stress-specific 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 disease susceptibility in response to either autoimmune challenge or viral infection.

The idea that stress orchestrates the movement of immune cells to peripheral targets has been explored previously2. Although 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 stress response has remained elusive. Poller et al.1 now provide insights into distinct signaling mechanisms that control the rapid mobilization of neutrophils into the 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 into the bone marrow requires the activation of the canonical controllers of the neuroendocrine response to stress, the corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). 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 in a leukocyte-autonomous fashion to enhance the function of CXC chemokine receptor 4 (CXCR4). CXCR4 has previously been described as a key player in the homing of cells to the bone marrow. This increase in leukocyte sequestration into the bone marrow has opposing effects on how the body responds to an autoimmune challenge versus a viral challenge.

Fig. 1: Linking stress circuits and immunity.
figure 1

An acute psychological stress activates distinct pathways and results in the mobilization of neutrophils into the general circulation and the movement of leukocytes from peripheral organs to the bone marrow. ACTH, adrenocorticotropic hormone; CORT, corticosterone; CRH, corticotropin releasing hormone.

By subjecting acutely stressed and unstressed mice to experimental autoimmune encephalomyelitis (EAE), Poller et al.1 show that stressed mice have lower clinical severity scores. These effects, which suggest 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 that lack CRH are more susceptible to EAE. Simply put, acute stress prevents the acquisition of autoimmunity.

The results are quite different when the system is challenged with a virus. Given the pandemic, this is particularly topical, so Poller et al.1 examined the effects of acute stress on viral infections. In comparison to age- and sex-matched controls exposed to SARS-CoV-2, stressed mice exposed to SARS-CoV-2 had higher viral titers. These effects were also dependent on corticosterone. Furthermore, this attenuation of the response to virus is not specific to SARS-CoV-2, as stress also increases viral titers after exposure to influenza A virus. The main lesson is that acute stress during the early phase of virus exposure impairs host adaptive immunity against infections.

In addition to the movement of monocytes and lymphocytes from organs to bone marrow, the authors provide information about the rapid neutrophilia that is triggered by acute stress. This neutrophilia has been primarily linked to noradrenergic signaling2, but Poller et al.1 find that the sympathetic nervous system and specifically, adrenergic signaling does not have a role in stress-induced neutrophilia. Instead, they used optogenetics to reveal a circuit that requires projection neurons in the motor cortex, spinal projections and binding of CXC chemokine ligand 1 (CXCL1) to CXC chemokine receptor 2 (CXCR2) specifically in skeletal muscle. This involvement of descending motor pathways and muscle is very intriguing, and probably a consequence of the initiation of a defensive behavior. Whether other stressors would initiate a similar response is unclear, but two of the key defensive behaviors used by mice (freezing and escape) rely on intense contraction of the skeletal muscle. Whether this has a role in different immune responses is not explored.

The remarkable findings of Poller et al.1 add a crucial piece to the burgeoning knowledge base that implicates distinct brain circuits as essential components of the immune system. The idea that the brain is a functional effector of the immune system is not new3,4, but understanding how specific connections and signaling elements contribute to different elements of the immune response provides new and targeted opportunities for intervention. These findings also provide much needed granularity on the contributions of CRHPVN neurons to specific aspects of the immune response. In addition to leveraging neuroendocrine signals to control the trafficking of immune cells1,2, CRHPVN neurons also project to the splenic nerve to promote the formation of plasma cells as part of a T cell-dependent immune response5. These cells, however, are but one part of a larger constellation of cells and circuits that are pivotal for regulating the immune system in response to different challenges. For example, anti-inflammatory pathways controlled by the parasympathetic system modulate the response to endotoxin6 and vagal activity, by controlling the release of acetylcholine from T cells, control innate immune responses7.

This study sets the scene for many interesting future studies. Foremost among them are extending these data on acute stress to conditions of early-life stress and chronic stress. Considerable data suggest that early-life and chronic stress dysregulate both innate and adaptive immune responses by altering the balance of cytokines toward an inflammatory milieu8,9. The exact role of brain circuits in these altered immune mechanisms has not been determined. Studies that examine synapses in the paraventricular nucleus of the hypothalamus demonstrate that stressful experiences alters these synapses to undergo plasticity after stress10. It would be fascinating if altered neuroplasticity were linked to dysregulated immune responses.

It has also become clear that the gut microbiota has a pivotal role in modulating immune responses and stress alters the composition and metabolic profile of the gut microbiota11. The central circuitry that regulates the microbiota–immune–gut–brain axis is complex and whether this is involved in regulating leukocyte dynamics remains to be determined.

Another important future direction is to understand the role of the brain circuits in promoting resilience. Resilient individuals have different innate and adaptive immunophenotypes from that of stress-sensitive individuals, but there remains a paucity of studies that directly assess the role of brain circuitry involved in these differences. The elegant techniques used in by Poller et al.1 to directly determine how the brain regulates leukocyte dynamics can be applied to studies that examine the brain circuits that promote resilience.

As noted above, studies examining synapses in the paraventricular nucleus of the hypothalamus demonstrate that stressful experiences leave long-lasting changes in the ability of these synapses to undergo plasticity at distinct temporal windows after stress10. This scenario raises the provocative idea that brain signaling mechanisms responsible for changes in sensitivity to future stressors could contribute to dysregulated immune responses. Given exciting recent work that the brain can also form neuronal representations of inflammatory information and retrieve it to reactivate a state of peripheral immunity12, it is tantalizing to speculate on the potential contributions and health implications of central nervous system memory mechanisms to immunological memory.