Bacterial lipopolysaccharide (LPS), also known as endotoxin, is an intrinsic component of the cell walls of most gram-negative bacteria. Among the most important triggering molecules of innate immunity, LPS consists of 3 components:
The exact structures of each component vary among species of bacteria, but all are recognized by the innate immune system. The primary receptors are the toll-like receptors (TLRs), principally TLR4 and TLR2, which are expressed on macrophages, neutrophils, and dendritic cells, as well as on B cells and T cells. Lipid A is the most potent component, capable of activating effector cells at concentrations of a few picograms per milliliter.
The effects of LPS include activation of monocytes and neutrophils, leading to upregulation of genes for various cytokines (IL-1, IL-6, tumor necrosis factor [TNF]); degranulation; alternative pathway complement activation; and direct impact on the vascular endothelium. LPS is the major cause of shock, fever, and other pathophysiologic responses to bacterial sepsis, making it an important cause of morbidity and mortality during gram-negative bacterial infections. Interestingly, footpad injection of LPS in rodents results in an acute anterior uveitis. This animal model is called endotoxin-induced uveitis (EIU; see Chapter 4). See Clinical Examples 1-1 and 1-2.
Other bacterial cell wall components
The bacterial cell wall and membrane are complex. They contain numerous polysaccharide, lipid, and protein structures that can initiate an innate immune response independent of adaptive immunity. Killed lysates of many types of gram-positive bacteria or mycobacteria can directly activate macrophages, making them useful as adjuvants. Some of these components have been implicated in various models for arthritis and uveitis. In many cases, the molecular mechanisms might be similar to those of LPS.
Exotoxins and other secretory products of bacteria
Certain bacteria secrete products known as exotoxins into their surrounding microenvironment. Many of these products are enzymes that, although not directly inflammatory, can cause tissue damage and subsequent inflammation and tissue destruction. Examples of these products include
hemolysins such as streptolysin O, which can kill neutrophils by causing cytoplasmic and extracellular release of their granules
phospholipases such as the Clostridium perfringens α-toxins, which kill cells and cause necrosis by disrupting cell membranes
An intravitreal injection of a purified hemolysin BL toxin derived from Bacillus cereus can cause direct necrosis of retinal cells and retinal detachment. In animal studies, as few as 100 B cereus can produce enough toxin to cause complete loss of retinal function in 12 hours. In addition to being directly toxic, bacterial exotoxins can also be strong triggers of an innate immune response.
Callegan MC, Jett BD, Hancock LE, Gilmore MS. Role of hemolysin BL in the pathogenesis of extraintestinal Bacillus cereus infection assessed in an endophthalmitis model. Infect Immun. 1999;67(7):3357–3366.
Murphy K, Travers P, Walport M. Janeway’s Immunobiology. 8th ed. London: Garland Science; 2012.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.