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Innate Immunity: Inflammation I - Vocabulary Flashcards

Learning Objectives

  • Describe how micro-organism chemical structures can be recognized by specific cellular receptors.
  • Describe the mechanisms of cellular activation after recognition of PAMPs/DAMPs.
  • Discuss how PAMPs/DAMPs can trigger inflammation.

Overview: Innate Immunity and its Relationship with Adaptive Immunity

  • Innate immunity provides the first line of defense and can prevent infection or eliminate microbes before adaptive immunity develops.
  • Effector innate mechanisms can operate even during adaptive immune responses to help clear microbes.
  • Innate immunity not only fights microbes but also stimulates adaptive responses and can influence the nature of those responses to optimize effectiveness against different microbes.
  • Innate signals can shape subsequent adaptive responses to maximize their effectiveness against various pathogens.

Features of Innate Immunity and Recognition

  • Innate immunity recognizes structures characteristic of microbial pathogens that are not present on host (mammalian) cells.
  • The innate system has evolved to recognize microbial products that are often essential for microbial survival.
  • Receptors of the innate immune system (on white blood cells) are encoded germline (not somatically rearranged).

Self vs. Foreign and PAMPs/MAMPs

  • The innate system must distinguish self from foreign to differentiate healthy cells from pathogens.
  • Pathogen-Associated Molecular Patterns (PAMPs): structural features of microbes (bacteria, viruses, fungi, protozoa).
  • Microbe-Associated Molecular Patterns (MAMPs) are a related term used for microbe-associated patterns.
  • Innate recognition is based on PAMPs/MAMPs and Host Structure patterns; this recognition drives innate responses.

Microbial PAMPs Recognized (Diagrammatic Gram-Positive Context)

  • Bacterial components that can serve as PAMPs:
    • Flagellin protein (flagellum)
    • Capsule polysaccharides (capsule)
    • Peptidoglycan (cell wall) – especially in Gram-positive bacteria
    • Lipoteichoic acids (lipids associated with the cell wall in Gram-positive bacteria)
    • Certain lipoproteins
    • N-formyl peptides (cytoplasmic peptides released during infection)
    • Unmethylated DNA (bacterial DNA)
    • Pili (pili-associated proteins)
  • The diagram depicts a Gram-positive bacterium and associated PAMPs recognized by mammalian innate immunity receptors.

Pattern-Recognition Receptors (PRRs)

  • PAMPs/MAMPs are recognized by Pattern Recognition Receptors (PRRs).
  • PRR functions include:
    • Proinflammatory signal generation
    • Cytokine release
    • Phagocytosis stimulation
  • Major PRR families:
    • Toll-like receptors (TLRs)
    • NOD-like receptors (NLRs)
    • RIG-like receptors (RLRs)

Toll-like Receptors (TLRs)

  • TLRs are transmembrane proteins that recognize PAMPs.
  • Expressed on macrophages, dendritic cells, and mast cells (sentinel cells) and on epithelium exposed to the external environment.
  • Intracellular endosomal TLRs include TLR3, TLR7, and TLR9.
  • Each TLR detects a different set of PAMPs.
  • Signaling involves adaptor proteins such as MyD88 and TRIF (and TRAM for TRIF-dependent signaling).

TLR Ligands (PAMPs) and Their Receptors

  • TLR1: cell-surface – Triacylated lipoprotein (bacteria)
  • TLR2: cell-surface – Lipoproteins (bacteria, viruses, parasites)
  • TLR3: endosomal – dsRNA (viruses)
  • TLR4: cell-surface – Lipopolysaccharide (LPS) (bacteria, viruses)
  • TLR5: cell-surface – Flagellin (bacteria)
  • TLR6: cell-surface – Diacylated lipoprotein (bacteria, viruses)
  • TLR7: intracellular – ssRNA (viruses, bacteria)
  • TLR8: intracellular – ssRNA (viruses, bacteria)
  • TLR9: intracellular – CpG DNA (viruses, bacteria, protozoa)
  • TLR10: intracellular – Unknown
  • TLR11: cell-surface – Toxoplasma profilin-like molecule (protozoa)
  • TLR12 and TLR13: found in mice, not humans; unknown ligands
  • Location summary: cell surface TLRs recognize extracellular ligands; endosomal TLRs recognize nucleic acid PAMPs

TLR Signaling Pathways

  • Engagement of TLRs leads to intracellular signaling via adaptor molecules such as MyD88, TRAM, and TRIF.
  • End result is activation of transcription factors including NF-κB and IRF-3.
  • Example signaling scenarios:
    • TLR4 with LPS: activates both MyD88-dependent and TRIF-TRAM-dependent pathways, leading to NF-κB and IRF-3 activation respectively.
    • MyD88-dependent pathways promote proinflammatory cytokine production; TRIF-dependent pathways promote type I interferons via IRF-3.
  • Diagrammatic representation:
    • TLR4 + LPS
      ightarrow ext{MyD88-dependent signaling}
      ightarrow ext{NF-}
      \kappa B
      ightarrow ext{proinflammatory cytokines}
    • TLR4
      ightarrow ext{TRIF-TRAM-dependent signaling}
      ightarrow ext{IRF-3}
      ightarrow ext{type I IFN}

NOD-Like Receptors (NLRs)

  • NLRs are cytosolic (not membrane-bound) receptors and provide a second line of detection for bacteria/viruses that reach the cytoplasm.
  • Important members: NOD1 and NOD2; they sense bacterial peptidoglycans.
  • Signaling cascades activate NF-κB, leading to expression of proinflammatory cytokines and chemokines.
  • Diagram:
    • NOD1/NOD2
      ightarrow NF-\kappa B
      ightarrow ext{proinflammatory cytokines/chemokines}

RIG-I-like Receptors (RLRs)

  • RLRs are RNA helicases that detect viral RNA: short dsRNA or ssRNA with 5' triphosphate ends.
  • Intracellular signaling results in NF-κB activation and expression of type I interferons.
  • Diagram:
    • RLRs
      ightarrow NF-\kappa B + ext{type I IFN}

Other Mammalian Pattern-Recognition Receptors

  • Receptors include:
    • RLRs: RIG-1 (intracellular) – short dsRNA
    • NLRs: NOD1 (peptidoglycans), NOD2 (muramyl dipeptide)
    • CLRs (C-type lectin receptors, e.g., Dectin-1 binds glucans in fungi)
    • Other surface receptors: Mannose receptor (MR/CD206) – recognizes mannose, fucose, N-acetylglucosamine; involved in phagocytosis of bacterial PAMPs
    • CD14 – LPS recognition (co-receptor with TLR4)
    • Peptidoglycan recognition proteins
    • CD1 – glycolipids; CD36 – lipoproteins; CD48 – fimbriae
  • CLRs example: Dectin-1 binds glucans (fungal recognition)
  • Net idea: a broad family of PRRs expands detection to diverse microbial components.

Pattern-Recognition Receptors in Phagocytes

  • Phagocytic cells involved: Neutrophils, Macrophages, Dendritic Cells.
  • Key phagocytic receptor example: Mannose receptor (MR; CD206) which recognizes mannose, fucose, and N-acetylglucosamine residues on bacteria to promote phagocytosis.

Damage-Associated Molecular Patterns (DAMPs)

  • DAMPs are host (self) molecules released from damaged or necrotic cells that alert the immune system to tissue injury.
  • Two broad categories:
    • Extracellular DAMPs (released from damaged surroundings or degraded extracellular matrix): hyaluronic acid, heparan sulfate, fibrinogen, collagen-derived peptides, fibronectin, laminin, elastin.
    • Intracellular DAMPs (released from injured cells or exposed during necrosis): HMGB1, uric acid, chromatin, adenosine, galectins, S100 proteins, cathelicidins, defensins, N-formyl peptides, lactoferrin, heat-shock proteins.
  • Release mechanism: necrotic cell injury promotes extracellular release of DAMPs and subsequent danger signaling; routine apoptosis typically minimizes DAMP release.

High Mobility Group Box Protein-1 (HMGB1) as a DAMP

  • HMGB1 is a potent inducer of inflammation when released extracellularly.
  • It serves as an example of a DAMP and is associated with necrosis-driven inflammatory signaling.

Inflammasomes and Cytokine Maturation

  • Inflammasomes are key components of innate immunity that sense danger signals and coordinate inflammatory responses.
  • Activation leads to activation of the enzyme caspase-1.
  • Caspase-1 cleaves inactive cytokine precursors into their active forms:
    • Pro-IL-1β → IL-1β
    • Pro-IL-18 → IL-18
  • The overall interaction between PRR signaling and the inflammasome is synergistic: PAMPs and DAMPs can act together to induce robust inflammation.
  • Mechanistic summary:
    • PRR recognition of PAMPs/DAMPs → NF-κB–driven synthesis of pro-cytokines (e.g., pro-IL-1β, pro-IL-18)
    • Inflammasome assembly and caspase-1 activation → maturation and release of IL-1β and IL-18
    • Result: inflammatory cytokine and chemokine release to recruit and activate other immune cells

Summary: PAMPs, DAMPs, and the Inflammatory Cascade

  • DAMPs and PAMPs drive the inflammatory response via distinct but overlapping pathways:
    • PAMPs (derived from microbes) initiate signaling that leads to cytokine and chemokine production, mainly through NF-κB and IRF family transcription factors.
    • DAMPs (host-derived danger signals) often activate inflammasomes, resulting in caspase-1–mediated maturation of inflammatory cytokines.
  • The combined output includes chemokines (e.g., CXCL8/IL-8, CXCL10, CCL3, CCL4, CCL5), proinflammatory cytokines (IL-1, IL-6, IL-18, TNF-α), and type I interferons, which coordinate the recruitment and activation of innate immune cells and shape subsequent adaptive responses.
  • Representative cytokine and chemokine output (conceptual):
    • Proinflammatory cytokines: IL-1, IL-6, IL-18, TNF-α, IFN-γ
    • Chemokines: CXCL8/IL-8, CXCL10, CCL3, CCL4, CCL5
    • Lipid mediators: prostaglandins, leukotrienes, platelet-activating factor
  • Practical implications include understanding how excessive or misdirected PRR signaling can contribute to inflammatory diseases and how therapeutics might target specific PRRs or inflammasome components to modulate inflammation without compromising host defense.