|Kogut, Michael - Mike|
|He, Louis - Haiqi|
Submitted to: Developmental and Comparative Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 2/10/2005
Publication Date: 6/1/2005
Citation: Kogut, M.H., Iqbal, M., He, H., Philbin, V., Kaiser, P., Smith, A. 2005. Expression and function of toll-like receptors in chicken heterophils. Developmental and Comparative Immunology. 29:791-807. Interpretive Summary: During the first week of life after hatching, the baby chick must fight off bacterial infections such as Salmonella. We do not know how the chicks are able to see the bacteria and start their immune system to fight these germs. The objective of this experiment was to look at a specific white blood cell of the chicken, called the heterophil, and determine how the cells recognize bacteria and start their immune system. We found the heterophils have chemical structures on their surfaces that feel the presence of bacteria. Once they know the bacteria are present, the cells produce a series of chemicals that tell their immune system that the bacteria are there and help is needed. The results of this experiment are important to the pharmaceutical industry in the United States because we now know which chemicals are produced (or not) by the baby chick's cells of the immune system when they encounter Salmonella. Thus, we can now see if there are ways for us to get the baby chick to make these chemicals which will help the chick fight Salmonella infections.
Technical Abstract: For the first time, we have investigated the mRNA expression of a panel of Toll-like receptors (TLR) and their functions in chicken heterophils. Heterophils constitutively expressed TLR1/6, TLR2 type 1, TLR type 2, TLR3, TLR4, TLR5, and TLR7. Furthermore, among the various TLR agonists, flagellin (from Salmonella typhimuirum, FLG), peptidoglycan (from Staphylococcus aureus, PGN), ultra-pure lipopolysaccharide (from Salmonella minnesota, LPS), the synthetic double stranded DNA analog [poly (I:C)], and the guanosine analog, loxoribine (LOX) directly induced both an oxidative burst and a degranulation response. The only exception was the synthetic bacterial lipoprotein Pam3CSK4 (palmitoyl-3-cysteine-serine-lysine-4, PAM) that induced degranulation, but no oxidative burst. The bacterial TLR agonists (PAM, PGN, LPS, and FLG) all induced an up-regulation of expression of mRNA of the pro-inflammatory cytokines IL-1beta, IL-6, and IL-8; whereas both poly I:C and LOX induced a down-regulation of these cytokine mRNAs. Stimulation of heterophils with each specific TLR agonist led to a differential increase in the phosphorylation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation, but not the phosphorylation of c-Jun N-terminal kinase (JNK). The broad TLR expression profile in heterophils strongly reflects their principal role as first line effector cells in avian host defense against bacterial, viral, and fungal infections. Our results also imply that triggering of heterophil TLR3 [poly(I:C)] and TLR7 (LOX) systems represent a potentially important role against viral infections by the release of antiviral secretory granules. The results are also indicative of the differential stimulation of signaling pathways that regulate the oxygen-dependent and 'independent antimicrobial defense mechanisms of avian heterophils.