Innate Immune Cells and Pattern Recognition Receptors

Innate Immune Cells and Pattern Recognition Receptors (PRRs)

• Innate immune cells possess genetically programmed cell surface receptors that bind to unique molecular patterns on the surface of pathogens.
• These receptors are known as Pattern Recognition Receptors (PRRs).
• PRRs enable the innate immune system to distinguish between self and non-self by recognizing pathogen-associated molecular patterns (PAMPs) on microbes.
• The body does not produce PAMPs, which allows for the immune system to target foreign invaders.

Toll-like Receptors (TLRs)

• TLRs act like locks on the surface of innate immune cells that are ready to be opened by the appropriate PAMP "key".
• Most TLRs are located on the exterior of the cell, but some are intracellular.
• TLR4, found on macrophages, recognizes lipopolysaccharides (LPS) associated with gram-negative bacteria.
• TLR2 recognizes peptidoglycan patterns associated with gram-positive bacteria.
• Activation of TLRs results in the activation of the transcription factor NF-κB, which leads to the synthesis and secretion of cytokines.
• These cytokines promote inflammation and recruit other innate immune cells.

NF-κB Activation

• NF-κB is a critical transcription factor in the immune system.
• Activation of NF-κB is essential for coordinating the body's response to infection, injury, or stress.
• NF-κB helps initiate and regulate immune and inflammatory processes.
• When a PAMP binds to a TLR, a cascade of intracellular signaling pathways is initiated, activating NF-κB.
• One primary outcome of NF-κB activation is the transcription of genes that encode pro-inflammatory cytokines, like TNF-α, IL-1, IL-6, and IL-8.
• These cytokines induce inflammation and recruit other immune cells to the site of infection or injury, activating adaptive immune cells.
• NF-κB induces the expression of adhesion molecules on endothelial cells, enabling immune cells to adhere to blood vessels and migrate to infected or inflamed tissues.
• NF-κB activation enhances the ability of phagocytic cells to engulf and destroy pathogens.
• It promotes the formation of phagosomes and activates microbicidal enzymes that kill ingested microbes.
• NF-κB promotes cell survival by preventing apoptosis, allowing immune cells to survive long enough to clear the infection.
• NF-κB signaling amplifies the immune response and induces the expression of more receptors for inflammatory mediators.

Scavenger Receptors

• Scavenger receptors recognize and bind pathogen patterns associated with lipoproteins, polysaccharides, and some nucleic acids.
• Scavenger proteins are involved in phagocytosis and removing debris from host cells undergoing apoptosis.

Opsonin Receptors

• Opsonin receptors are located on phagocytic cells and bind to microbes that have been tagged through opsonization.
• Opsonized bacteria are tagged with complement proteins like C3b and C4b.
• Phagocytic cells contain PRRs such as complement receptor 3 (CR3) and CR4.
• These receptors attract the phagocyte to the microbe and reduce the possibility of escape.

Summary of Innate Immune Response

• Innate immune cells, like macrophages, have PRRs that bind PAMPs on invading microbes and non-self antigens.
• Upon the macrophage recognizing a microbial surface pattern, the recognition of PRR and PAMP activates the macrophage.
• Phagocytosis proceeds by ingesting and digesting the microbe through the phagolisosome and antimicrobial metabolic activity.
• The digested microbe activates NF-κB and the secretion of pro-inflammatory cytokines.
• Microbicidal enzymes are released, and other immune cells are recruited.
• This process leads to antigen presentation and lymphocyte activation.

Events After PAMPs Bind to PRRs

• PAMP binding to PRRs like TLRs triggers a series of responses aimed at detecting, responding to, and clearing pathogens.
• PAMPs recognized by PRRs initiate an intracellular signaling cascade.
• Adaptor proteins activate downstream signaling proteins, which activate several transcription factors, including NF-κB.
• NF-κB translocates to the nucleus, driving the transcription of genes involved in inflammation, immune response, and antimicrobial defense.
• Cytokines such as TNF-α, IL-1, IL-6, and IL-12 are produced and secreted, promoting inflammation and recruiting immune cells to the site of infection.
• Chemokines, like IL-8 (CXCL8) and MCP-1, are produced to recruit immune cells to the site of infection.
• TLR activation can enhance the ability of macrophages and neutrophils to engulf pathogens and trigger the release of phagocytic receptors.
• Immune cells produce antimicrobial peptides (AMPs), like defensins, to directly kill pathogens.
• Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced to damage and kill engulfed pathogens.
• PRR activation can trigger the complement system, enhancing pathogen recognition, opsonization, and destruction.
• In response to viral infections, some PRRs lead to the production of type I interferons (e.g., IFN-α, IFN-β).
• TLR signaling helps dendritic cells mature and migrate to lymph nodes, where they can present processed pathogen antigens to T cells.
• Activation of TLRs on dendritic cells leads to the upregulation of co-stimulatory molecules necessary for T cell activation.
• Cytokines like IL-1, TNF-α, and IL-6 not only mediate inflammation but also promote tissue repair processes.
• In some cases, activated PRRs may promote programmed cell death (apoptosis) to prevent the spread of infection or remove damaged cells.

Key Outcomes of PAMP-PRR Binding

• PRRs bind to PAMPs, signaling that an infection is present.
• This leads to the production of pro-inflammatory cytokines, enhancing the inflammatory response.
• Phagocytosis is enhanced, and other immune cells are recruited.
• The complement system is activated, marking pathogens for destruction.
• Dendritic cells help link the innate immune response with the adaptive immune system by presenting antigens to T cells.
• Inflammatory cytokines promote healing processes.

Examples of PRRs and Associated PAMPs

• TLR3 on the surface of immune cells binds double-stranded RNA, resulting in the production of interferon and antiviral cytokines.
• TLR5 on the surface of immune cells binds the protein flagellin, located on the surface of bacterial flagella, resulting in the activation of phagocytosis and secretion of cytokines.

PAMPs vs. DAMPs

• PAMPs are derived from microorganisms and drive inflammation in response to infections.
• Lipopolysaccharide (LPS) is a well-known PAMP found on the outer cell wall of gram-negative bacteria.
• DAMPs are derived from host cells, including tumor cells, dead or dying cells, or products released from cells in response to signals such as hypoxia.

Sub-types of PRRs

• Pattern recognition receptors (PRRs) recognize specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells.
• PRRs bridge nonspecific and specific immunity, producing nonspecific anti-infection, antitumor, and other immunoprotective effects.
• Most PRRs in the innate immune system of vertebrates are classified into five types: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs).
• PRRs are composed of ligand recognition domains, intermediate domains, and effector domains.

Learn about innate immune cells and pattern recognition receptors (PRRs). Understand how PRRs enable the innate immune system to distinguish between self and non-self by recognizing pathogen-associated molecular patterns (PAMPs) on microbes. Explore Toll-like Receptors (TLRs) and their role in pathogen recognition.