Cytokines are systemic effectors of lymphatic function in acute inflammation

Abstract

The response of the lymphatic system to inflammatory insult and infection is not completely understood. Using a near-infrared fluorescence (NIRF) imaging system to noninvasively document propulsive function, we noted the short-term cessation of murine lymphatic propulsion as early as 4h following LPS injection. Notably, the effects were systemic, displaying bilateral lymphatic pumping cessation after a unilateral insult. Furthermore, IL-1β, TNF-α, and IL-6, cytokines that were found to be elevated in serum during lymphatic pumping cessation, were shown separately to acutely and systemically decrease lymphatic pulsing frequency and velocity following intradermal administration. Surprisingly, marked lymphatic vessel dilation and leakiness were noted in limbs contralateral to IL-1β intradermal administration, but not in ipsilateral limbs. The effects of IL-1β on lymphatic pumping were abated by pre-treatment with an inhibitor of inducible nitric oxide synthase, L-NIL (N-iminoethyl-L-lysine). The results suggest that lymphatic propulsion is systemically impaired within 4h of acute inflammatory insult, and that some cytokines are major effectors of lymphatic pumping cessation through nitric oxide-mediated mechanisms. These findings may help in understanding the actions of cytokines as mediators of lymphatic function in inflammatory and infectious states.

Keywords: CD14/TLR4/MD2; CD14/Toll-like receptor 4/MD2; ICG; IFN-γ; IL; Inflammation; Interleukin-1 beta; Interleukin-6; L-NIL; LECs; LPS; Lymphatic; MCP-1/CCL2; N-iminoethyl-L-lysine; NIRF; T helper 1-type; Th1-type; Tumor necrosis factor-alpha; iNOS; indocyanine green; inducible nitric oxide; interferon-gamma; interleukin; lipopolysaccharide; lymphatic endothelial cells; monocyte chemoattractant protein-1/chemokine (C–C motif) ligand 2; near-infrared fluorescence imaging.