Endogenous TNFα orchestrates the trafficking of neutrophils into and within lymphatic vessels during acute inflammation

Abstract

Neutrophils are recognised to play a pivotal role at the interface between innate and acquired immunities following their recruitment to inflamed tissues and lymphoid organs. While neutrophil trafficking through blood vessels has been extensively studied, the molecular mechanisms regulating their migration into the lymphatic system are still poorly understood. Here, we have analysed neutrophil-lymphatic vessel interactions in real time and in vivo using intravital confocal microscopy applied to inflamed cremaster muscles. We show that antigen sensitisation of the tissues induces a rapid but transient entry of tissue-infiltrated neutrophils into lymphatic vessels and subsequent crawling along the luminal side of the lymphatic endothelium. Interestingly, using mice deficient in both TNF receptors p55 and p75, chimeric animals and anti-TNFα antibody blockade we demonstrate that tissue-release of TNFα governs both neutrophil migration through the lymphatic endothelium and luminal crawling. Mechanistically, we show that TNFα primes directly the neutrophils to enter the lymphatic vessels in a strictly CCR7-dependent manner; and induces ICAM-1 up-regulation on lymphatic vessels, allowing neutrophils to crawl along the lumen of the lymphatic endothelium in an ICAM-1/MAC-1-dependent manner. Collectively, our findings demonstrate a new role for TNFα as a key regulator of neutrophil trafficking into and within lymphatic system in vivo.

Distinct neutrophil counts and functions in newly diagnosed type 1 diabetes, latent autoimmune diabetes in adults, and type 2 diabetes

“…The discrepancy might be due to the fact that many other factors can affect the process of neutrophil migration. Previous studies indicated that tumour necrosis factor, intercellular cell adhesion molecule‐1, and IL‐6 can play a positive role in neutrophil migration . In this study, our RNA‐Seq analysis showed that the expression of these genes as well as neutrophils chemo‐attractants including CXCL8, CXCL1, CXCL2, CXCL3, and CXCL16 were decreased in T1D patients when compared with healthy controls.…”

“…Previous studies indicated that tumour necrosis factor, intercellular cell adhesion molecule-1, and IL-6 can play a positive role in neutrophil migration. [32][33][34] In this study, our RNA-Seq analysis showed that the expression of these genes as well as neutrophils chemo-attractants including CXCL8, CXCL1, CXCL2, CXCL3, and CXCL16 were decreased in T1D patients when compared with healthy controls. Therefore, many other molecules in addition to CD62L may act together to mediate neutrophil migration.…”

Potential Protective Effects of the Water‐Soluble Chinese Propolis on Hypertension Induced by High‐Salt Intake

“…Several studies have reported that an influx of neutrophils characterizes inflammation into the inflammatory area in which the cytokines play a crucial role. 22 our results indicate that WPS reduces the HS-induced inflammatory response. It could be hypothesized that WPS can protect vascular endothelial function by reducing the production of proinflammatory cytokines like IL-6 and TNF-α and decreasing the oxidative stress of inflammatory factors.…”

Organ-specific lymphatic vasculature: From development to pathophysiology

“…Neutrophil migration relies on lymphocyte function–associated antigen 1, an integrin/complement receptor CD11b and C-X-C or C-C chemokine receptors CXCR4 and/or CCR7 ( Fig. 1 C ; Gorlino et al, 2014 ; Hampton et al, 2015 ; Arokiasamy et al, 2017 ). Dermis also contains an abundant population of macrophages, which contributes to local control of lymphangiogenesis and lymphatic remodeling during development, inflammation, and wound healing ( Harvey and Gordon, 2012 ; Kim et al, 2014 ).…”