Peptidoglycan recognition protein genes and risk of Parkinson's disease

Increased gut permeability, inflammation, and colonic α‐synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case‐control studies were genotyped for 30 single‐nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5'untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95%CI 0.4‐0.9], CC OR 0.15 [95%CI 0.04‐0.6]; log‐additive P‐trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD. © 2014 International Parkinson and Movement Disorder Society     

Toll-like receptors mediate induction of peptidoglycan recognition proteins in human corneal epithelial cells

Human peptidoglycan recognition proteins (PGLYRPs) are a novel family of pattern recognition receptors, and also act as anti-bacterial proteins. This study was to explore the toll-like receptor (TLR)-mediated regulation of PGLYRPs in human corneal epithelial cells (HCECs). Fresh human donor corneoscleral tissues were used to prepare cryosections. Primary HCECs, established from limbal explants, were treated with microbial ligands to TLRs 1-9 for 4-48 h, with or without pretreatment of TLR antibodies, NFkB inhibitor, or siRNA transfection. The mRNA of PGLYRPs was evaluated by RT and real-time PCR, and their proteins and NFkB activation were determined by immunostaining and Western blot. The nuclear IRF3 activity was quantified using an ELISA-based TransAM kit. PGLYRP-2, -3 and -4 were found to be expressed by human corneal epithelium while PGLYRP-1 was not detected. In primary HCEC cultures, PGLYRP-3 and -4 were constitutively expressed while PGLYRP-2 was largely inducible. PGLYRP-2 was induced by bacterial components, Pam3CSK4, PGN, flagellin and FSL-1, ligands for TLR2/1, 2, 5 and 2/6, respectively. Interestingly, PGLYRP-2 was strongest stimulated by polyI:C representing viral dsRNA. TLR3 antibody or NFkB inhibitor blocked IRF3 and NFkB p65 activation as well as polyI:C-stimulated PGLYRP-2. RNA interference indicates that the polyI:C-induced PGLYRP-2 was dramatically blocked in the cells transfected with siRNA-TRIF but neither siRNA-MyD88 nor the negative control siRNA-F. These findings suggest that human corneal epithelium may response to viral or bacterial infection by producing PGLYRPs through TLRs, and the induction of PGLYRP-2 by dsRNA was through TLR3-TRIF-IRF3-NFkB signaling pathways.     

The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases

Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.     

Assessment of microbiota and peptidoglycan in perianal fistulas

Transanal advancement flap repair has been advocated as the treatment of choice for high transsphincteric perianal fistulas, but fails in 1 of every 3 patients. Persistence of the fistula after flap repair might be the result of ongoing disease in the remaining fistula tract. In 10 specimens of the distal part of the fistula, microbiota was assessed by means of conventional microbiological culture and 16S rRNA gene sequencing. Proinflammatory bacterial peptidoglycan and recognition proteins were assessed by immunohistochemistry. Bacterial species were bowel derived, skin derived, or a combination of both. No mycobacterium species were identified. 16S rRNA gene sequencing failed to identify bacteria in all but 1 specimen, most likely as a result of low numbers of organisms. Peptidoglycan was detected in 90% of the patients, and a host response to peptidoglycan in 60%. Therefore, we suggest that peptidoglycan might play a role in the ongoing inflammation in perianal fistulas.     

Genetic susceptibility to Kawasaki disease: analysis of pattern recognition receptor genes

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology occurring in infants and children. Several lines of evidence suggested the importance of genetic factors and infectious triggers for the pathogenesis of KD. We have reported that oral administration of a pure NOD1 ligand induces coronary arteritis in mice without fail. Since NOD1 is one of the pattern recognition receptors (PRRs) which play important roles in the innate immunity for the detection of microbial substances and induce inflammatory responses, we have investigated the association of PRR genes with the development of KD. Forty-six tagging-SNPs in 19 PRR genes were genotyped in Japanese KD patients (n=356, consisting of two groups) and controls (n=215). The genotypes and allele frequencies of each SNP or haplotype were compared between KD patients and controls. As a result, we did not find any genes with strongly contributed to the development of KD. A haplotype, G-T-C-C, in the NOD1 gene, was associated with lower risk for KD development (KD 1st group versus controls: 23.2% versus 35.3%, Pc=0.0385). The second-round case-control study in KD group 2 demonstrated that a haplotype, T-T-C-G-A-C, in the NLRP1 gene was associated with a higher risk for KD development (4.9% versus 1.2%, Pc=0.035). From the association analysis of SNPs and haplotypes of 19 PRR genes, NOD1 and NLRP1 seemed to partly contribute to the development of KD. Further analysis with larger samples of another independent set would be needed to find confirmative results.     

Peptidoglycan: a critical activator of the mammalian immune system during infection and homeostasis

Peptidoglycan is a conserved structural component of the bacterial cell wall with molecular motifs unique to bacteria. The mammalian immune system takes advantage of these properties and has evolved to recognize this microbial associated molecular pattern. Mammals have four secreted peptidoglycan recognition proteins, PGLYRP-1-4, as well as two intracellular sensors of peptidoglycan, Nod1 and Nod2. Recognition of peptidoglycan is important in initiating and shaping the immune response under both homeostatic and infection conditions. During infection, peptidoglycan recognition drives both cell-autonomous and whole-organism defense responses. Here, we examine recent advances in the understanding of how peptidoglycan recognition shapes mammalian immune responses in these diverse contexts.