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An Ancient Defense Mechanism: Why Are PRRs Known as the Original Guards of the Immune System?
In the vast universe of the immune system, pattern recognition receptors (PRRs) undoubtedly play a crucial role. These receptors are important sensors in host cells that recognize pathogen-specific molecules and protect our health. In the ancient history of evolution, PRRs are known as the original guardians of the immune system because they evolved before the emergence of the adaptive immune system.
PRRs are encoded by the host's genome and sense molecules released by pathogens and host cells upon damage or death.
PRRs are mainly expressed by innate immune system cells such as dendritic cells, macrophages, monocytes and neutrophils, and are also expressed by epithelial cells. They recognize two types of molecules: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs include bacterial carbohydrates, nucleic acids, and bacterial peptides, while DAMPs are endogenous signals released by host cells during damage or death, such as uric acid and extracellular ATP.
Diversity and functions of PRR
According to whether they are located in the cell membrane or within the cell, PRRs can be divided into membrane-bound receptors and cytoplasmic receptors. Among them, membrane-bound receptors include Toll-like receptors (TLRs) and C-type lectin receptors (CLRs). Cytoplasmic receptors such as NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) mainly function within cells.
Toll-like receptor (TLR)
TLRs are a class of membrane proteins capable of recognizing extracellular or endocytosed pathogen patterns. The structural features of these receptors are leucine-rich repeats (LRR). They can trigger cells to produce and secrete cytokines and initiate various immune defense programs. So far, 10 functional TLRs have been identified in humans, each of which can interact with specific PAMPs.
Signaling pathway
When TLRs are activated, they dimerize and initiate cellular responses through MyD88-dependent or TRIF-dependent signaling pathways. MyD88-dependent signaling involves the interaction of multiple proteins, ultimately leading to the secretion of pro-inflammatory cytokines. Therefore, TLRs are critical elements in both the innate and adaptive immune systems.
C-type lectin receptor (CLR)
CLRs are widely diverse and expressed by many cells of the innate immune system. These receptors mainly use sugars as the molecules they recognize and can recognize a variety of pathogens including fungi. Although CLRs are called lectins, many members don't target just sugars. Therefore, the capabilities of the CLR are much more complex than its name suggests.
NOD-like receptor (NLR) and RIG-I-like receptor (RLR)
NLRs mainly exist within cells and can recognize bacterial peptidoglycan and activate pro-inflammatory and antimicrobial immune responses. RLR is mainly related to the recognition of viral RNA and can initiate antiviral signals.
Clinical significance
In clinical research, the role of PRRs is not limited to immune defense, but also extends to the treatment of cancer, infection, neurodegenerative diseases and other fields. In immunotherapy, researchers are exploring how to harness the autonomous immune system to treat various diseases, and the signal transduction pathways of some PRRs have been shown to be related to the development of various diseases.
Research shows that dysfunction of certain PRRs can lead to the development of cancer, prompting us to re-evaluate the potential of these receptors in the medical field.
For example, mutations in NOD2 are related to the onset of Crohn's disease, and regulating its signaling pathway may become a therapeutic direction. In addition, PRRs are also associated with infection by oncogenic factors in the intestine, such as Helicobacter pylori, indicating the importance of these receptors in cancer immune surveillance.
With a deeper understanding of the functions of PRRs, we have reason to believe that these ancient defense mechanisms will become increasingly important in future clinical applications. These receptors are not only the original gatekeepers of the immune system, they may also be a critical bridge between human health and disease. So how can we make the most of these ancient defense mechanisms to address current and future health challenges?
