Peptidoglycan recognition proteins (PGRPs) are a family of innate pattern recognition molecules that bind bacterial
peptidoglycan. While the role of PGRPs in Drosophila innate immunity has been extensively studied, how the four mammalian PGRP
proteins (PGLYRP1 to PGLYRP4) contribute to host defense against bacterial pathogens in vivo remains poorly understood. PGLYRP1, PGLYRP3, and PGLYRP4 are directly bactericidal in vitro, whereas PGLYRP2 is an N-acetylmuramyl-
L-alanine amidase that cleaves
peptidoglycan between the
sugar backbone and the
peptide stem. Because PGLYRP2 cleaves muramyl
peptides detected by host
peptidoglycan sensors Nod1 and Nod2, we speculated that PGLYRP2 may act as a modifier of Nod1/Nod2-dependent innate immune responses. We investigated the role of PGLYRP2 in Salmonella enterica serovar Typhimurium-induced
colitis, which is regulated by Nod1/Nod2 through the induction of an early Th17 response. PGLYRP2 did not contribute to expression of Th17-associated
cytokines,
interleukin-22 (IL-22)-dependent antimicrobial
proteins, or inflammatory
cytokines. However, we found that Pglyrp2-deficient mice displayed significantly enhanced
inflammation in the cecum at 72 h postinfection, reflected by increased polymorphonuclear leukocyte (PMN) infiltration and goblet cell depletion. Pglyrp2 expression was also induced in the cecum of Salmonella-infected mice, and expression of
green fluorescent protein under control of the Pglyrp2 promoter was increased in discrete populations of intraepithelial lymphocytes. Lastly, Nod2(-/-) Pglyrp2(-/-) mice displayed increased susceptibility to
infection at 24 h postinfection compared to Pglyrp2(-/-) mice, which correlated with increased PMN infiltration and submucosal
edema. Thus, PGLYRP2 plays a protective role in vivo in the control of S. Typhimurium
infection through a Nod1/Nod2-independent mechanism.