Circulating myeloid-derived MMP8 in stress susceptibility and depression

Flurin Cathomas, Hsiao Yun Lin, Kenny L. Chan, Long Li, Lyonna F. Parise, Johana Alvarez, Romain Durand-de Cuttoli, Antonio V. Aubry, Samer Muhareb, Fiona Desland, Yusuke Shimo, Aarthi Ramakrishnan, Molly Estill, Carmen Ferrer-Pérez, Eric M. Parise, C. Matthias Wilk, Manuella P. Kaster, Jun Wang, Allison Sowa, William G. JanssenSara Costi, Adeeb Rahman, Nicolas Fernandez, Matthew Campbell, Filip K. Swirski, Eric J. Nestler, Li Shen, Miriam Merad, James W. Murrough, Scott J. Russo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. 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.

Original languageEnglish
Pages (from-to)1108-1115
Number of pages8
JournalNature
Volume626
Issue number8001
DOIs
StatePublished - 29 Feb 2024

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