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Circulating myeloid-derived MMP8 in stress susceptibility and depression.
- Source :
-
Nature [Nature] 2024 Feb; Vol. 626 (8001), pp. 1108-1115. Date of Electronic Publication: 2024 Feb 07. - Publication Year :
- 2024
-
Abstract
- Psychosocial stress has profound effects on the body, including the immune system and the brain <superscript>1,2</superscript> . 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) <superscript>3</superscript> , 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
Extracellular Space metabolism
Mice, Inbred C57BL
Nucleus Accumbens metabolism
Nucleus Accumbens pathology
Parenchymal Tissue metabolism
Single-Cell Gene Expression Analysis
Social Behavior
Social Isolation
Depressive Disorder, Major blood
Depressive Disorder, Major enzymology
Depressive Disorder, Major genetics
Depressive Disorder, Major metabolism
Matrix Metalloproteinase 8 blood
Matrix Metalloproteinase 8 deficiency
Matrix Metalloproteinase 8 genetics
Matrix Metalloproteinase 8 metabolism
Monocytes chemistry
Monocytes immunology
Monocytes metabolism
Stress, Psychological blood
Stress, Psychological genetics
Stress, Psychological immunology
Stress, Psychological metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 626
- Issue :
- 8001
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38326622
- Full Text :
- https://doi.org/10.1038/s41586-023-07015-2