Toll-like Receptor 4 Reduces Chronic Airway Inflammation

John W. Hollingsworth, MD, David A. Schwartz, MD, MPH, and Donald N. Cook, Ph.D.
Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center
K08ES12717, T32ES7031, U19ES12496, U19ES11375, R01ES07498, and P30ES11961

NIEHS scientists and colleagues at Duke University report in the May 15 edition of the Journal of Immunology progress in understanding the complex relationship between asthma and air-way inflammation associated with exposure to endotoxin. The research model employed in their study will be useful in further understanding the regulation of allergic airway inflammation and ”should facilitate the development of novel therapies to treat asthma by augmenting natural regulatory mechanisms.”

Endotoxin, also known as lipopolysaccharide, is a component of the cell walls of gram-negative bacteria and is commonly found in household dust. Exposure to endotoxin has been shown to exacerbate asthma; however exposure early in life has also been shown to be protective against the development of asthma. The latter finding is a component of a controversial theory known as the ”hygiene hypothesis,” which states that an excessively clean environment in early childhood may predispose some people towards asthma, allergies and autoimmune diseases.

The researchers exposed normal mice and mice lacking the gene for the toll-like receptor 4 (tlr4) to the chicken egg protein albumin containing small amounts of endotoxin and studied allergic responses. Results showed similar responses for both kinds of mice after short-term exposures. However, the tlr4-deficient mice showed much stronger pulmonary allergic responses compared with the normal mice when the allergic challenges lasted for greater than one week.

These findings demonstrate that tlr4 signaling is necessary to regulate inflammatory responses to ongoing allergic challenges. The investigators conclude that their work supports previous epidemiologic findings that ”low doses of endotoxin, particularly in childhood, protect against developing asthma later in life.

Citation: Hollingsworth JW, Whitehead GS, Lin KL, Nakano H, Gunn MD, Schwartz DA, Cook DN. TLR4 signaling attenuates ongoing allergic inflammation. J Immunol. 2006 May 15;176(10):5856-62.