Yanyan Xu; Hanan Slimani; Klaus Fersching, Edward Mark, Thomas Baumbusch, Robert Tanaka, Daniel Jakobsson, Min Lee
Received March 26, 2019; Accepted June 30, 2019; Published September 20, 2019
Abstract
We described the key observations in a systematic essay that presents data pointing to the role of Neisseria meningitidis in mediating a pro-inflammatory response in human PMN, together with novel findings that begin to unravel the crosstalk between TLR-2 and JNK in these professional phagocytes. Sialylation of meningococcal endotoxin before addition to human PMN led to A-LOS sialic acid chain-dependent upregulation of pro-inflammatory cytokines and chemokines which occurred from as early as 4 hours post-LOS addition. This suggested a role for LOS in the recruitment of PMN in individuals presenting with the early symptoms of systemic meningococcal disease. Different LOS modifications, namely O-Acetylation and S-modification, elicited different cytokine responses due to a possible difference in the TLR-4 compared to TLR-2 and -4 of the A-LOS sialic acid chain region of the endotoxin. Signalling pathways activated in THP1 cells, a transformed human macrophage cell line were potential markers of the two LOS receptors TLR-2 and -4 can also be activated by the phosphorylated sites within proteins such as ML that are released from the cell membrane upon PMN activation and degradation. Determination of the phosphorylated residues that determine the LOS end point(s) in the pro-inflammatory signalling pathways of TANK-binding kinase I (TBK-1), p38, I-jB a, and JNK showed that an s-LOS proinflammatory response depended on the interaction between TLR-2 and JNK as this kinase differed in the phosphorylated residues of p38 TANK-binding kinase I p38 and I-jB a in the ML experiments following TLR-2 blocking antibody treatment at LOS concentrations that were shown to be different in the ML p38 experiments. As expected, the TLR-4 antibody reduced both LOS v 3 mLmA-LOS pro-inflammatory responses as the receptor also interacted with the JNK kinase.
Keywords: N. meningitidis, PMN, TLR, Proinflammatory cytokines, JNK, MyD88
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