Premium
Toll‐Like Receptor 4 (TLR4) Myeloid Differentiation Factor‐2 (MD‐2) Complex
Author(s) -
Tetzlaff Sarah,
Larson Mary,
Toll Molly,
Garb Jodie,
Tourdot Ben,
Newman Debra K.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb172
Subject(s) - tlr4 , sepsis , lipopolysaccharide , toll like receptor , immunology , immune system , septic shock , myeloid , receptor , medicine , innate immune system
Sepsis, the tenth leading cause of death in the United States, is a whole‐body inflammatory response to infection. Sepsis leads to septic shock, a condition with a 30–40% mortality rate caused by multiple organ failure and development of hypotension. Lack of understanding of the pathophysiology of sepsis limits successful treatment options. Gram‐negative bacteria are a major cause of sepsis. The outer membrane of Gram‐negative bacteria contains lipopolysaccharide (LPS). LPS is recognized by a receptor complex expressed by certain immune cells that includes the transmembrane glycoprotein, Toll‐like receptor 4 (TLR4), and myeloid differentiation factor‐2 (MD‐2). Over‐stimulation of immune cells by LPS through TLR4/MD‐2 results in sepsis. TLR4‐mediated activation of immune cells is also responsible for allergic contact dermatitis due to nickel, a common and less fatal condition than sepsis. The crystal structure of TLR4‐MD‐2‐LPS has elucidated residues involved in LPS binding to TLR4/MD‐2 and in TLR4 dimerization, which are essential events involved in immune cell activation and induction of sepsis. A better understanding of interactions between TLR4, LPS and MD‐2 will help create better drugs to disrupt the interactions. The Laconia SMART (Students Modeling A Research Topic) Team used 3‐D printing technology to model the TLR4 dimer in collaboration with MSOE. Supported by a grant from the NIH‐NCRR‐SEPA.