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. Janssen, Sara Costi, Adeeb Rahman, Nicolas Fernandez, Matthew Campbell, Filip K. Swirski, Eric J. Nestler, Li Shen, Miriam Merad, James W. Murrough and Scott J. Russo ()
Additional contact information
Flurin Cathomas: Icahn School of Medicine at Mount Sinai
Hsiao-Yun Lin: Icahn School of Medicine at Mount Sinai
Kenny L. Chan: Icahn School of Medicine at Mount Sinai
Long Li: Icahn School of Medicine at Mount Sinai
Lyonna F. Parise: Icahn School of Medicine at Mount Sinai
Johana Alvarez: Icahn School of Medicine at Mount Sinai
Romain Durand- de Cuttoli: Icahn School of Medicine at Mount Sinai
Antonio V. Aubry: Icahn School of Medicine at Mount Sinai
Samer Muhareb: Icahn School of Medicine at Mount Sinai
Fiona Desland: Icahn School of Medicine at Mount Sinai
Yusuke Shimo: Icahn School of Medicine at Mount Sinai
Aarthi Ramakrishnan: Icahn School of Medicine at Mount Sinai
Molly Estill: Icahn School of Medicine at Mount Sinai
Carmen Ferrer-Pérez: Icahn School of Medicine at Mount Sinai
Eric M. Parise: Icahn School of Medicine at Mount Sinai
C. Matthias Wilk: Icahn School of Medicine at Mount Sinai
Manuella P. Kaster: Federal University of Santa Catarina
Jun Wang: Icahn School of Medicine at Mount Sinai
Allison Sowa: Icahn School of Medicine at Mount Sinai
William G. Janssen: Icahn School of Medicine at Mount Sinai
Sara Costi: Icahn School of Medicine of Mount Sinai
Adeeb Rahman: Icahn School of Medicine at Mount Sinai
Nicolas Fernandez: Icahn School of Medicine at Mount Sinai
Matthew Campbell: Trinity College Dublin
Filip K. Swirski: Icahn School of Medicine at Mount Sinai
Eric J. Nestler: Icahn School of Medicine at Mount Sinai
Li Shen: Icahn School of Medicine at Mount Sinai
Miriam Merad: Icahn School of Medicine at Mount Sinai
James W. Murrough: Icahn School of Medicine at Mount Sinai
Scott J. Russo: Icahn School of Medicine at Mount Sinai

Nature, 2024, vol. 626, issue 8001, 1108-1115

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-07015-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:626:y:2024:i:8001:d:10.1038_s41586-023-07015-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-07015-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().