Editing Peptidoglycan (section)

=== Receptors ===
[[Innate immune system]] senses intact peptidoglycan and peptidoglycan fragments using numerous PRRs ([[pattern recognition receptor]]s) that are secreted, expressed intracellularly or expressed on the cell surface.<ref name="Wolf-2018" />

==== Peptidoglycan recognition proteins ====
[[Peptidoglycan recognition protein|PGLYRPs]] are conserved from [[insect]]s to [[mammal]]s.<ref name="Bastos-2021" /> Mammals produce four secreted soluble peptidoglycan recognition proteins ([[Peptidoglycan recognition protein 1|PGLYRP-1]], [[Peptidoglycan recognition protein 2|PGLYRP-2]], [[Peptidoglycan recognition protein 3|PGLYRP-3]] and [[Peptidoglycan recognition protein 4|PGLYRP-4]]) that recognize muramyl pentapeptide or tetrapeptide.<ref name="Wolf-2018" /> They can also bind to [[Lipopolysaccharide|LPS]] and other molecules by using binding sites outside of the peptidoglycan-binding groove.<ref name="Sun-2022" /> After recognition of peptidoglycan, PGLYRPs activate [[polyphenol oxidase]] (PPO) molecules, Toll, or immune deficiency (IMD) signalling pathways. That leads to production of [[antimicrobial peptides]] (AMPs).<ref name="Sun-2022" />

Each of the mammalian PGLYRPs display unique tissue expression patterns. PGLYRP-1 is mainly expressed in the granules of [[neutrophil]]s and [[eosinophil]]s.<ref name="Wolf-2018" /> PGLYRP-3 and 4 are expressed by several tissues such as skin, sweat glands, eyes or the intestinal tract.<ref name="Bastos-2021" /> PGLYRP-1, 3 and 4 form disulphide-linked [[homodimers]] and [[heterodimers]] essential for their bactericidal activity.<ref name="Bastos-2021" /> Their binding to bacterial cell wall peptidoglycans can induce bacterial cell death by interaction with various bacterial transcriptional regulatory proteins.<ref name="Wolf-2018" /> PGLYRPs are likely to assist in bacterial killing by cooperating with other PRRs to enhance recognition of bacteria by phagocytes.<ref name="Wolf-2018" />

PGLYRP-2 is primarily expressed by the [[liver]] and secreted into the circulation.<ref name="Wolf-2018" /> Also, its expression can be induced in skin [[keratinocyte]]s, oral and intestinal [[Epithelium|epithelial]] cells.<ref name="Bastos-2021" /> In contrast with the other PGLYRPs, PGLYRP-2 has no direct bactericidal activity. It possesses peptidoglycan amidase activity, it hydrolyses the lactyl-amide bond between the [[MurNAc]] and the first amino acid of the stem peptide of peptidoglycan.<ref name="Wolf-2018" /><ref name="Bastos-2021" /> It is proposed, that the function of PGLYRP-2 is to prevent over-activation of the immune system and [[inflammation]]-induced tissue damage in response to [[NOD2]] ligands (see below), as these muropeptides can no longer be recognized by NOD2 upon separation of the peptide component from MurNAc.<ref name="Bastos-2021" /> Growing evidence suggests that peptidoglycan recognition protein family members play a dominant role in the [[Tolerance to infections|tolerance]] of intestinal epithelial cells toward the commensal microbiota.<ref name="Sun-2022" /><ref>{{cite journal | vauthors = Liang Y, Yang L, Wang Y, Tang T, Liu F, Zhang F | title = Peptidoglycan recognition protein SC (PGRP-SC) shapes gut microbiota richness, diversity and composition by modulating immunity in the house fly Musca domestica | journal = Insect Molecular Biology | pages = 200–212 | date = December 2022 | volume = 32 | issue = 2 | pmid = 36522831 | doi = 10.1111/imb.12824 | s2cid = 254807823 }}</ref> It has been demonstrated that expression of PGLYRP-2 and 4 can influence the composition of the intestinal [[microbiota]].<ref name="Sun-2022" />

Recently, it has been discovered, that PGLYRPs (and also NOD-like receptors and peptidoglycan transporters) are highly expressed in the developing mouse [[brain]].<ref name="Gonzalez-Santana-2020">{{cite journal | vauthors = Gonzalez-Santana A, Diaz Heijtz R | title = Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior | journal = Trends in Molecular Medicine | volume = 26 | issue = 8 | pages = 729–743 | date = August 2020 | pmid = 32507655 | doi = 10.1016/j.molmed.2020.05.003 | s2cid = 219539658 | url = https://hal.archives-ouvertes.fr/hal-03492013/file/S1471491420301325.pdf }}</ref> PGLYRP-2 and is highly expressed in [[neuron]]s of several brain regions including the [[prefrontal cortex]], [[hippocampus]], and [[cerebellum]], thus indicating potential direct effects of peptidoglycan on neurons. PGLYRP-2 is highly expressed also in the cerebral cortex of young children, but not in most adult cortical tissues. PGLYRP-1 is also expressed in the brain and continues to be expressed into adulthood.<ref name="Gonzalez-Santana-2020" />

==== NOD-like receptors ====
Probably the most well-known receptors of peptidoglycan are the [[NOD-like receptor]]s (NLRs), mainly [[NOD1]] and [[NOD2]]. The NOD1 receptor is activated after iE-DAP (γ-d-glutamyl-meso-diaminopimelic acid) binding, while NOD2 recognizes MDP (muramyl dipeptide), by their [[LRR domain]]s.<ref name="Sun-2022" /> Activation leads to self-oligomerization, resulting in activation of two signalling cascades. One triggers activation of [[NF-κB]] (through RIP2, [[MAP3K7|TAK1]] and [[IκB kinase|IKK]]<ref name="Murphy-2017">{{Cite book | vauthors = Murphy K, Weaver C, Janeway C |title=Janeway's immunobiology |year=2017 |isbn=978-0-8153-4505-3 |edition=9th |location=New York |publisher=Garland Science |pages=45, 96–98 |oclc=933586700}}</ref>), second leads to [[Mitogen-activated protein kinase|MAPK]] signalling cascade. Activation of these pathways induces production of inflammatory [[cytokine]]s and [[chemokine]]s.<ref name="Wolf-2018" />

NOD1 is expressed by diverse cell types, including myeloid phagocytes, epithelial cells<ref name="Wolf-2018" /> and neurons.<ref name="Gonzalez-Santana-2020" /> NOD2 is expressed in monocytes and macrophages, epithelial intestinal cells, [[Paneth cell]]s, [[dendritic cell]]s, [[osteoblast]]s, keratinocytes and other epithelial cell types.<ref name="Bastos-2021" /> As [[cytosol]]ic sensors, NOD1 and NOD2 must either detect bacteria that enter the cytosol, or peptidoglycan must be degraded to generate fragments that must be transported into the cytosol for these sensors to function.<ref name="Wolf-2018" />

Recently, it was demonstrated that [[NLRP3]] is activated by peptidoglycan, through a mechanism that is independent of NOD1 and NOD2.<ref name="Bastos-2021" /> In macrophages, N-acetylglucosamine generated by peptidoglycan degradation was found to inhibit hexokinase activity and induce its release from the [[Mitochondrion|mitochondrial]] [[membrane]]. It promotes NLRP3 [[inflammasome]] activation through a mechanism triggered by increased mitochondrial membrane permeability.<ref name="Bastos-2021" />

[[NLRP1]] is also considered as a cytoplasmic sensor of peptidoglycan. It can sense MDP and promote [[Interleukin-1 family|IL-1]] secretion through binding NOD2.<ref name="Sun-2022" /><ref name="Bersch-2021" />

==== C-type lectin receptors (CLRs) ====
[[C-type lectin]]s are a diverse superfamily of mainly Ca<sup>2+</sup>-dependent proteins that bind a variety of [[carbohydrate]]s (including the glycan skeleton of peptidoglycan), and function as innate immune receptors.<ref name="Bastos-2021" /> CLR proteins that bind to peptidoglycan include MBL ([[Mannose-Binding Lectin|mannose binding lectin]]), [[ficolin]]s, [[REG3A|Reg3A]] (regeneration gene family protein 3A) and PTCLec1.<ref name="Sun-2022" /> In mammals, they initiate the [[Lectin pathway|lectin-pathway]] of the [[Complement system|complement]] cascade.<ref name="Bastos-2021" />

==== Toll-like receptors ====
The role of [[Toll-like receptor|TLRs]] in direct recognition of peptidoglycan is controversial.<ref name="Wolf-2018" /> In some studies, has been reported that peptidoglycan is sensed by [[Toll-like receptor 2|TLR2]].<ref>{{cite journal | vauthors = Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D | title = Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2 | journal = Journal of Immunology | volume = 163 | issue = 1 | pages = 1–5 | date = July 1999 | doi = 10.4049/jimmunol.163.1.1 | pmid = 10384090 | s2cid = 23630870 | doi-access = free }}</ref> But this TLR2-inducing activity could be due to cell wall [[lipoprotein]]s and [[lipoteichoic acid]]s that commonly co-purify with peptidoglycan. Also variation in peptidoglycan structure in bacteria from species to species may contribute to the differing results on this topic.<ref name="Wolf-2018" /><ref name="Bastos-2021" />