Circulating myeloid-derived MMP8 in stress susceptibility and depression

Area of Science:

• Neuroscience
• Immunology
• Psychiatry

Background:

• Psychosocial stress impacts the immune system and brain.
• Mechanisms linking peripheral immune changes to stress disorders like MDD are unclear.

Purpose of the Study:

• Investigate the role of circulating myeloid cell-specific proteinase, MMP8, in stress-related disorders.
• Elucidate the mechanism by which peripheral immune factors influence central nervous system function and behavior under stress.

Main Methods:

• Measured MMP8 serum levels in humans with MDD and stress-susceptible mice.
• Utilized mass cytometry and single-cell RNA sequencing for immune cell phenotyping.
• Assessed neurophysiological and behavioral changes in mice following chronic social defeat stress (CSDS).

Main Results:

• MMP8 expression is elevated in MDD patients and CSDS mice.
• Increased MMP8 alters extracellular space and neurophysiology in the nucleus accumbens (NAc) of mice.
• Depleting MMP8 reversed stress-induced behavioral and neurophysiological changes.

Conclusions:

• Peripheral MMP8 infiltrates the brain, affecting NAc structure and function.
• This establishes a pathway for peripheral immunity influencing CNS and behavior in stress.
• MMP8 presents a potential therapeutic target for stress-related neuropsychiatric disorders.