Peptidoglycan recognition protein-peptidoglycan complexes increase monocyte/macrophage activation and enhance the inflammatory response.

Peptidoglycan recognition proteins (PGRP) are pattern recognition receptors that can bind or hydrolyse peptidoglycan (PGN). Four human PGRP have been described: PGRP-S, PGRP-L, PGRP-Iα and PGRP-Iß. Mammalian PGRP-S has been implicated in intracellular destruction of bacteria by polymorphonuclear cells, PGRP-Iα and PGRP-Iß have been found in keratinocytes and epithelial cells, and PGRP-L is a serum protein that hydrolyses PGN. We have expressed recombinant human PGRP and observed that PGRP-S and PGRP-Iα exist as monomer and disulphide dimer proteins. The PGRP dimers maintain their biological functions. We detected the PGRP-S dimer in human serum and polymorphonuclear cells, from where it is secreted after degranulation; these cells being a possible source of serum PGRP-S. Recombinant PGRP do not act as bactericidal or bacteriostatic agents in the assayed conditions; however, PGRP-S and PGRP-Iα cause slight damage in the bacterial membrane. Monocytes/macrophages increase Staphylococcus aureus phagocytosis in the presence of PGRP-S, PGRP-Iα and PGRP-Iß. All PGRP bind to monocyte/macrophage membranes and are endocytosed by them. In addition, all PGRP protect cells from PGN-induced apoptosis. PGRP increase THP-1 cell proliferation and enhance activation by PGN. PGRP-S-PGN complexes increase the membrane expression of CD14, CD80 and CD86, and enhance secretion of interleukin-8, interleukin-12 and tumour necrosis factor-α, but reduce interleukin-10, clearly inducing an inflammatory profile.

Uptake and intracellular trafficking of superantigens in dendritic cells.

Bacterial superantigens (SAgs) are exotoxins produced mainly by Staphylococcus aureus and Streptococcus pyogenes that can cause toxic shock syndrome (TSS). According to current paradigm, SAgs interact directly and simultaneously with T cell receptor (TCR) on the T cell and MHC class II (MHC-II) on the antigen-presenting cell (APC), thereby circumventing intracellular processing to trigger T cell activation. Dendritic cells (DCs) are professional APCs that coat nearly all body surfaces and are the most probable candidate to interact with SAgs. We demonstrate that SAgs are taken up by mouse DCs without triggering DC maturation. SAgs were found in intracellular acidic compartment of DCs as biologically active molecules. Moreover, SAgs co-localized with EEA1, RAB-7 and LAMP-2, at different times, and were then recycled to the cell membrane. DCs loaded with SAgs are capable of triggering in vitro lymphocyte proliferation and, injected into mice, stimulate T cells bearing the proper TCR in draining lymph nodes. Transportation and trafficking of SAgs in DCs might increase the local concentration of these exotoxins where they will produce the highest effect by promoting their encounter with both MHC-II and TCR in lymph nodes, and may explain how just a few SAg molecules can induce the severe pathology associated with TSS.