Peptidoglycan recognition proteins in the brain: Role in neuroinflammation and behavioral consequences

Peptidoglycan recognition proteins (PGRPs) constitute an evolutionarily conserved family of pattern recognition molecules that detect bacterial peptidoglycan. While their antimicrobial functions have been well characterized in peripheral immunity, recent discoveries have unveiled critical roles for PGRPs in central nervous system inflammation and behavior. Among the four mammalian PGRP family members, PGLYRP1 exhibits unique expression in brain microglia and demonstrates potent pro-inflammatory properties in neurological contexts. Recently, PGLYRP1 has been shown to function as a key amplifier of neuroinflammation through a novel TREM1-Syk-Erk1/2-Stat3 signaling axis, establishing a positive feedback loop with TNF-α that perpetuates microglial activation. This review synthesizes current understanding of PGRP biology in the nervous system, with particular emphasis on molecular mechanisms of PGLYRP1, cellular sources, and behavioral consequences. We examine the structural basis of peptidoglycan recognition, cell-type-specific expression patterns, signaling pathways, and integration with other innate immune systems. Furthermore, we explore emerging connections between gut microbiome-derived peptidoglycan, blood-brain barrier penetration, and neuropsychiatric disorders. Critical knowledge gaps remain regarding physiological versus pathological roles of PGLYRP1, therapeutic targeting strategies, and translational potential. Understanding PGLYRP1-mediated neuroinflammation provides novel mechanistic insights into microbiome-brain communication and offers promising therapeutic avenues for neuroinflammatory and neurodegenerative diseases.