Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

Autor: Cathomas F; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Lin HY; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Chan KL; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Li L; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Durand-de Cuttoli R; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Parise LF; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Aubry AV; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Muhareb S; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Desland F; Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, USA., Shimo Y; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Ramakrishnan A; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Estill M; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Ferrer-Pérez C; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Parise EM; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wang J; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sowa A; Microscopy CoRE and Advanced Bioimaging Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Janssen WG; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Microscopy CoRE and Advanced Bioimaging Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Costi S; Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine of Mount Sinai, New York, NY, USA., Rahman A; Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, USA., Fernandez N; Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, USA., Swirski FK; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Nestler EJ; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Shen L; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Merad M; Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, USA., Murrough JW; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine of Mount Sinai, New York, NY, USA., Russo SJ; Nash Family Department of Neuroscience, Brain & Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2023 Jan 30. Date of Electronic Publication: 2023 Jan 30.
DOI: 10.21203/rs.3.rs-1647827/v1
Abstrakt: Psychosocial stress has profound effects on the body, including the peripheral 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) 3,4,5 , the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) 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), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control 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 novel 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.
Databáze: MEDLINE
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