Interleukin 17A (IL-17) is the signature cytokine produced by TH17 cells and has been implicated in host defense against infection and the pathophysiology of autoimmunity and cardiovascular disease. Little is known, however, about the influence of IL-17 on endothelial activation and leukocyte influx to sites of inflammation. We hypothesized that IL-17 would induce a distinct pattern of endothelial activation and leukocyte recruitment when compared to the TH1 cytokine, IFNγ. We found that IL-17 alone had minimal activating effects on cultured endothelium, while the combination of TNFα and IL-17 produced a synergistic increase in the expression of both P-selectin and E-selectin. Using intravital microscopy of the mouse cremaster muscle, we found that TNFα and IL-17 also led to a synergistic increase in E-selectin dependent leukocyte rolling on microvascular endothelium in vivo. In addition, TNFα and IL-17 enhanced endothelial expression of the neutrophilic chemokines CXCL1, CXCL2, and CXCL5, and led to a functional increase in leukocyte transmigration in vivo and CXCR2-dependent neutrophil but not T-cell transmigration in a parallel-plate flow chamber system. By contrast, endothelial activation with TNFα and IFNγ preferentially induced the expression of the integrin-ligands ICAM1 and VCAM1, as well as the T-cell chemokines CXCL9, CXCL10, and CCL5. These effects were further associated with a functional increase in T-cell but not neutrophil transmigration under laminar shear flow. Overall, these data show that IL-17 and TNFα act in a synergistic manner to induce a distinct pattern of endothelial activation that sustains and enhances neutrophil influx to sites of inflammation.

Neutrophils are the all-terrain vehicle of the innate immune system because of their ability to gain entry into tissues and organs, and thus, play an essential role in host defense. Exactly how this marvel of nature works is still incompletely understood. In the last two to three years, new players and processes have been identified in the endothelial - leukocyte adhesion cascade. Novel signaling pathways have been discovered in both the endothelium and the neutrophil that regulate various steps in the recruitment process. This review focuses on these emerging pathways and the mechanisms that regulate neutrophil recruitment across endothelium.

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