Innate Immunity and Cardiometabolic Disease

Innate Immunity and Cardiometabolic Disease Innate immunity, an ancient form of host defense, is the body’s rapid, first-line response to environmental threats, such as microbial infection. In contrast to the adaptive immune system—which is present only in higher-order vertebrates, and mediated primarily by somatically generated receptors—the innate immune system relies inherently on basic detection machineries coded for and conserved within the germ-lines of higher and lower organisms, from plants and fruits flies to mammals. For the specificity of innate immune receptors to be conferred genetically, innate immune recognition must be built on small families of membrane receptors that recognize highly conserved pattern structures present in large groups of microorganisms. Perhaps the most prominent and widely studied subgroup of these pattern recognition receptors is the toll-like receptor (TLR) family, whose 10 members are manifested in humans as cell surface receptors in a series of trouble-detecting sentinel cells. Individual TLRs are known to play important roles in the recognition of structures derived from pathogens, such as fungi, protozoa, viruses, and bacteria. As such, the TLR family is now widely accepted as the major microbe sensing system in mammals. A classic starting point for innate immunity is TLR-4, which—through detection of bacterial lipopolysaccharide—is crucial for the effective immune response to Gram-negative bacteria. The binding of lipopolysaccharide to TLR-4 leads to downstream activation of nuclear factor-κB (NF-κB), a nuclear transcription factor responsible for regulating gene products that initiate a generalized inflammatory response. Specifically, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and other proinflammatory mediators are all synthesized and released into the systemic circulation, where they trigger the activation of the complement system, the coagulation cascade, and the acute phase response. TNF-α and IL-1β also play key roles in facilitating leukocyte migration by increasing the expression of adhesion molecules on endothelial cells. Finally, the presence of circulating inflammatory cytokines enhances tissue perfusion, vascular permeability, and cell migration throughout the body. Altogether, these systemic changes work together to allow for the timely and efficient eradication of the invading microorganism. Inappropriate or sustained triggering of innate immunity and inflammatory signaling may, however, contribute to various medical conditions and diseases. Excessive activation of inflammatory cytokines leads to septic shock, a leading cause