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Cited by 189Tryptophan and brain disordersStress Responses and CortisolNeuroinflammation and Neurodegeneration Mechanisms

Circulating myeloid-derived MMP8 in stress susceptibility and depression

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Cathomas, Flurin, Lin, Hsiao-Yun, Chan, Kenny L., Li, Long, Parise, Lyonna F., Alvarez, Johana, Durand-de Cuttoli, Romain, Aubry, Antonio V. +22 more·2024·Nature
DOI 10.1038/s41586-023-07015-2PMC PMC10901735

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Abstract

Psychosocial stress has profound effects on the body, including the immune system and the brain 1,2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD) 3 , the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

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  • Increased IL-6 levels within the central nervous system may be associated with reduced synthesis of endothelial tight junction proteins claudin-5 and occludin, compromising blood-brain barrier integrity, which contributes to psychological abnormalities such as depression and anxiety.

    “As a pro-inflammatory cytokine, the increase in IL-6 levels within the central nervous system may also be associated with reduced synthesis of endothelial tight junction proteins, such as claudin-5 and occludin [21,22], which compromises the integrity of the blood–brain barrier. This, in turn, contributes to various psychological abnormalities or disorders, such as depression and anxiety.”

    From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [21]

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Cited by

Sorted by citations

Authors
Cathomas, F., Lin, H.-Y., Chan, K. L., Li, L., Parise, L. F., Alvarez, J., Durand-de Cuttoli, R., Aubry, A. V., Muhareb, S., Desland, F., Shimo, Y., Ramakrishnan, A., Estill, M., Ferrer-Pérez, C., Parise, E. M., Wilk, C. M., Kaster, M. P., Wang, J., Sowa, A., Janssen, W. G., Costi, S., Rahman, A., Fernandez, N., Campbell, M., Swirski, F. K., Nestler, E. J., Shen, L., Merad, M., Murrough, J. W., & Russo, S. J.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Tisch Cancer Institute (US)
  • Universidade Federal de Santa Catarina (BR)
  • Trinity College Dublin (IE)
Corresponding author
  • Cathomas, Flurin
  • Russo, Scott J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-02-07
Volume
626
Issue
8001
Pages
1108-1115
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-07015-2
PMC
PMC10901735
OpenAlex
W4391617513
Cited by
189
References
31
Citations by year
2026: 71 · 2025: 77 · 2024: 40 · 2023: 1
FWCI
27.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, cc-by-nc)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Science Foundation
  • Leon Levy Foundation
  • Icahn School of Medicine at Mount Sinai
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (30609, 31140, 31194, 30894, 186708, 30233)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Swiss Cancer Research Foundation
  • National Institutes of Health (1s10od026880-01, 1s10od030463-01)
  • Canadian Institutes of Health Research
  • National Heart, Lung, and Blood Institute (P01HL131478, P01HL142494)
  • National Institute of Mental Health (R01MH114882, R01MH051399, R01MH104559, R01MH127820, R01MH129306, R01MH133299)
  • National Institute on Drug Abuse (K99DA058213)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K99DK137037, P30DK020541)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
matrix metalloproteinase-8, depression, chronic social defeat stress, stress vulnerability, circulating monocytes, extracellular space, nucleus accumbens, peripheral immune cells, neuroinflammation, stress-related neuropsychiatric disorders, therapeutic target

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