TLR4 and Bacterial Endotoxin

One of the best characterized systems of innate immune activation is the Toll-Like-Receptor (TLR) 4. TLR4 is a membrane receptor in phagocytes that is specialized to identify bacterial lipopolysaccharides (LPS). LPS is a key part of the cell membrane of Gram-negative bacteria, which has endotoxin properties. Endotoxins are generally associated with pathogenicity and are a key part of the virulence of known periodontal pathogens, such as the red complex bacteria P. gingivalis, T. denticola, T. forsythia. The key tissue resident surveilling cells of the innate immune system are called macrophages (Figure 3a). The name macrophages comes from the Greek “macro-” meaning “large” and “-phage” meaning “eater”. This is descriptive of the characteristics of the macrophage as a key phagocytic cell that can engulf large bacteria or particles up to its relative size of ~10um. The critical activity that is necessary for the macrophage to eat the invading pathogens and eliminate the danger is recognition. Recognition is critical for activation of both effector and signaling downstream responses. Specialized complexes called Pattern Recognition Receptors (PRRs) exist on the macrophage including the TLR4 membrane receptor. Each receptor is highly specialized to identify specific Pathogen-Associated Molecular Patterns (PAMPs), which in the case of TLR4 is LPS. In response when a macrophage’s TLR4 recognizes LPS, it initiates the phagocytic process and secretes inflammatory cytokines. One of the key functions of these cytokines is to rapidly recruit immune cells from the circulation which serve as a backup to clear the threat. For instance, IL-8 is a well-established chemokine signal that recruits neutrophils from the circulation. Through diapedesis, the process of transmigration of blood cells to the tissue that results in extravasation these neutrophils follow the IL-8 gradient to the site of inflammation and employ their phagocytic capacities and robust oxidative burst capabilities to contribute to pathogen clearance (Figure 3b). Monocytes are also recruited to the area and become differentiated to macrophages to further support the battle against invading pathogens. During this process the dilation of capillaries and extravasation of cells and fluid to the tissues results in the typical calor, rubor and tumor that clinically manifest as redness and swelling of the gingival tissues. If the host cells can effectively clear the microbial challenge leading to pathogen removal, the pro-inflammatory signaling ceases and an equilibrium is again established to support homeostasis (Figure 3c).

Figure 3a.
Figure 3b.
Figure 3c.

Innate immunity includes the following component parts:

  • External barriers such as skin, oral mucosa, body secretions and even endogenous (normal) microbial inhabitants
  • Physiological factors as body pH and temperature
  • Blood and tissue leukocytes (neutrophils, monocytes, macrophages, mast cells, basophils, eosinophils and natural killer cells)
  • Dendritic cells for immune surveillance and antigen presentation
  • Primary and secondary lymphoid tissue
  • Soluble mediators of inflammation including acute phase proteins, complement and cytokines

The adaptive or acquired immune response system is mediated by T and B lymphocytes which are commonly referred to as T Cells and B Cells. There are three important characteristics to adaptive immunity:

  • Self-recognition (or recognition of non-self)
  • Specificity
  • Memory