Local coordination verses systemic disregulation: complexities in leukocyte recruitment revealed by local and systemic activation of TLR4 in vivo

The recruitment of leukocytes to a tissue is a critical step in the inflammatory response. Toll‐like receptor 4 (TLR4) is an important receptor involved in the initiation of inflammatory responses. Administration of the ligand for TLR4, lipopolysaccharide, is often used to model inflammation—local responses to stimuli within a specific tissue and systemic responses such as those observed during endotoxic or septic shock. Here, we review work, which demonstrates that in response to local activation of TLR4, highly coordinated and multistep processes are initiated, ultimately resulting in the leukocyte’s arrival at the inflamed tissue. In contrast, systemic activation of TLR4 results in nonspecific accumulation of leukocytes within the lung capillaries and liver sinusoids through mechanisms profoundly different than those involved in local tissue recruitment. Contrary to current dogma, leukocyte accumulation in the lung is dependent on endothelial rather than leukocyte activation. Finally, we discuss recent evidence suggesting that activation of leukocytes through TLR4, although still in the circulation, effectively paralyzes inflammatory cells, rendering them incapable of appropriate trafficking to inflamed tissues.