Brain motor and fear circuits regulate leukocytes during acute stress

• Published in: Nature (London) Vol. 607; no. 7919; pp. 578 - 584
• Main Authors: Poller, Wolfram C., Downey, Jeffrey, Mooslechner, Agnes A., Khan, Nargis, Li, Long, Chan, Christopher T., McAlpine, Cameron S., Xu, Chunliang, Kahles, Florian, He, Shun, Janssen, Henrike, Mindur, John E., Singh, Sumnima, Kiss, Máté G., Alonso-Herranz, Laura, Iwamoto, Yoshiko, Kohler, Rainer H., Wong, Lai Ping, Chetal, Kashish, Russo, Scott J., Sadreyev, Ruslan I., Weissleder, Ralph, Nahrendorf, Matthias, Frenette, Paul S., Divangahi, Maziar, Swirski, Filip K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2022; Nature Publishing Group
• Subjects: 13; 13/1; 13/31; 13/44; 14; 14/1; 14/34; 14/35; 14/63; 59; 631/250/371; 631/378/2607; 631/378/371; Animals; Autoimmunity; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - immunology; Brain; Brain - cytology; Brain - physiology; Chemokines; Chemokines - immunology; Circuits; Corticotropin-releasing hormone; COVID-19 - immunology; Disease Susceptibility; Fear - physiology; Genetics; Glucocorticoids; Glucocorticoids - metabolism; Humanities and Social Sciences; Humans; Hypothalamus; Immune response; Immune system; Immunity; Influenza; Information processing; Innate immunity; Leukocytes; Leukocytes (neutrophilic); Leukocytes - cytology; Leukocytes - immunology; Lymphocytes; Lymphocytes - cytology; Lymphocytes - immunology; Lymphoid Tissue - cytology; Lymphoid Tissue - immunology; Mice; Monocytes; Monocytes - cytology; Monocytes - immunology; Motor Neurons - cytology; Motor Neurons - physiology; multidisciplinary; Muscles; Nervous system; Neural Pathways; Neurons; Neutrophils; Neutrophils - cytology; Neutrophils - immunology; Optics; Optogenetics; Organs; Orthomyxoviridae Infections - immunology; Paraventricular Hypothalamic Nucleus - physiology; Psychological stress; SARS-CoV-2 - immunology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Signal transduction; Skeletal muscle; Stress, Psychological - immunology; Stress, Psychological - physiopathology; Viral diseases
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-04890-z

The nervous and immune systems are intricately linked 1 . Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood 2 . Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats. Distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, calibrating the ability of the immune system to respond to physical threats.