High endothelial venules at the nexus of an IL-6/gp130/STAT3 axis controlling immune surveillance during fever (173.22)

Abstract

Abstract Fever remains the least understood component of acute inflammation although it confers a survival benefit in endothermic and ectothermic vertebrates. Here we show that LPS- or turpentine-induced fever enhances immune surveillance by augmenting lymphocyte trafficking via high endothelial venules (HEV) in lymph nodes. We identified an autocrine feed-forward loop during the effector phase of fever in which IL-6 produced by HEV acts via the gp130 signal transducing subunit of the IL-6 receptor to enhance ICAM-1-dependent lymphocyte trafficking. Comparative analysis of the thermal response in gp130Y757F and gp130ΔSTAT mutant mice implicated STAT3/1 in the pathway downstream of fever that controls lymphocyte trafficking. An obligate role for STAT3 signaling was further delineated using Stat1-/- mice. While gp130-dependent MEK1-ERK1/2 signaling was not required for enhanced lymphocyte trafficking, ERK1/2 activation was necessary for the metalloproteinase-dependent shedding mechanism that restores endothelial ICAM-1 to homeostatic levels during the resolution phase of inflammation. Finally, thermally-induced lymphocyte trafficking across HEV lowered the threshold for antigen-driven priming of naïve T cells in lymph nodes. Taken together, these studies provide insight into a novel IL-6/gp130/STAT3 axis that acts as a highly integrated thermally-sensitive alert system to heighten immune surveillance during febrile responses.