The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants

Abstract

Lipopolysaccharide (LPS, endotoxin) is a structural component of the gram-negative outer membrane. The lipid A moiety of LPS binds to the LPS receptor complex expressed by leukocytes, endothelial cells, and parenchymal cells and is the primary component of gram-negative bacteria that is recognized by the immune system. Activation of the LPS receptor complex by native lipid A induces robust cytokine production, leukocyte activation, and inflammation, which is beneficial for clearing bacterial infections at the local level but can cause severe systemic inflammation and shock at higher challenge doses. Interestingly, prior exposure to LPS renders the host resistant to shock caused by subsequent LPS challenge, a phenomenon known as endotoxin tolerance. Treatment with lipid A has also been shown to augment the host response to infection and to serve as a potent vaccine adjuvant. However, the adverse effects associated with the pronounced inflammatory response limit the use of native lipid A as a clinical immunomodulator. More recently, analogs of lipid A have been developed that possess attenuated proinflammatory activity but retain attractive immunomodulatory properties. The lipid A analog monophosphoryl lipid A exhibits approximately 1/1,000th of the toxicity of native lipid A but retains potent immunoadjuvant activity. As such, monophosphoryl lipid A is currently used as an adjuvant in several human vaccine preparations. Because of the potency of lipid A analogs as immunoadjuvants, numerous laboratories are actively working to identify and develop new lipid A mimetics and to optimize their efficacy and safety. Based on those characteristics, lipid A analogs represent an attractive family of immunomodulators.

Figure 1

Generic structure of lipopolysaccharide. Lipopolysaccharide is comprised of three major structural components, the outward facing O-specific chain, the core segment that links the O-specific chain to lipid A and the lipid A component that embeds in the outer membrane of Gram negative bacteria.

Figure 2

LPS receptor signaling pathways. Activation of the LPS receptor complex induces TLR4 dimerization/oligomerization with rapid activation of the MyD88-depedent signaling pathways as described in the text. Activated TLR4 is then endocytosed and the TRIF-dependent signaling pathway is induced.

Figure 3

Molecular structures of native E. coli lipid A and monophosphoryl lipid A. MPLA is produced either de novo or by hydrolysis of native diphosphoryl lipid A, leading to the removal of one phosphate group and altered fatty acid side chains, resulting in a conformation with substantially reduced toxicity.

Figure 4

Cellular mechanisms by which TLR4 agonists mediate immunoadjuvant functions. TLR4 agonists facilitate T cell clonal expansion and activation by augmenting cytokine production and antigen presentation. The augmentation of Th1 polarity and activation facilitates B cell immunoglobulin production.