Release, Cytokine leads to Infiltration, Inflammatory cells

Binding of damage- or pathogen-associated molecular patterns (DAMPs or PAMPs) to pattern recognition receptors (PPRs) such as toll-like receptors (TLRs) can lead to the activation of, amongst others, nuclear factor-κB (NF-κB) or the transcription factor AP-1. This leads to an upregulation of chemokines and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukins or proteases ^[1][2]. TLRs are found expressed in most cells, including liver cells such as hepatocytes, Kupffer cells (KCs) or hepatic stellate cells (HPCs) ^[2]. Upon cytokine secretion, polymorphonuclear neutrophils (PMNs) that, amongst others, circulate in the blood, can become attracted. PMNs are potent phagocytes, but they also lead to pathogen destruction upon oxidative bursting and are for their part capable of pro-inflammatory cytokine production as well. Various endothelial adhesion molecules, such as the intercellular adhesion molecule 1 (ICAM-1), mediate neutrophil adhesion to endothelial cells. ICAM-1 expression on the luminal surface of the capillary is increased during inflammation, and interacts with ß2 integrin, which is expressed on the surface of PMN. Subsequent to adhesion, neutrophils begin to migrate across the endothelium and towards the center of inflammation ^[3][4]. Interleukin-8 (IL-8) is known to be one of the most potent chemoattractants for the recruitment and activation of neutrophils into various organs (e.g. lung, intestine), and binds to the human CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2) on the surface of the PMN ^[5][6][7]. But not only IL-8, also macrophage inflammatory protein-2 (MIP-2), growth-regulated oncogenes-α, -β, and -γ, as well as the rodent peptides cytokine-induced neutrophil chemoattractant and KC are all members of the CXC subfamily of chemokines and chemoattractants for inflammatory cells^[8]

Cullen and co-workers could further confirm the importance of specific chemokines for chemotaxis of different inflammatory cells. They depleted certain chemokines by using respective antibodies in supernatants of Fas-stimulated HeLa cells (see Relationship:924 for explanation on Fas and its role on cytokine induction) and subsequently assessed the chemotactic activity of immune cells. Only depletion of MCP-1 was sufficient to block almost all THP-1 monocyte chemotaxis. On the other hand, chemotaxis of primary human peripheral blood neutrophils was depending mainly on secreted IL-8. Using an in vivo mouse model, the authors found that Fas stimulation could trigger phagocyte migration by administration of anti-Fas (Jo2) antibody into C57BL/6 mice within 10 h of anti-Fas administration. This correlated with extensive cell death in the thymus and a dramatic increase of CD11b-positive macrophages in the same tissue^[9].

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

This KER can be described quantitatively, as useful chemotaxis-assays are available that make use of isolated immune cells ex vivo. Those results give an indication on concentrations necessary for cell migration, but need to be carefully considered with regards to direct transferability to the in vivo situation. Moreover, not only IL-8 is responsible for the recruitment of neutrophils, but also other chemokines can contribute to attraction of inflammatory cells. However, additional proof for this KER is provided by the neutralization of chemokines, which prevented a further onset of inflammation.

^[8]: mouse ^[9][10]: human