Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Abstract

The acute phase of the inflammatory response involves an increase in the concentrations of different plasma proteins that include fibrinogen (Fbg) and multiple proinflammatory mediators. In parallel, neutrophil activation is thought to play a crucial role in several inflammatory conditions, and it has been recently demonstrated that Fbg specifically binds to the α-subunit of CD11b/CD18 on neutrophil surface. Although several reports have shown that CD11b engagement modulates neutrophil responses, the effect of human Fbg (hFbg), one of CD11b physiologic ligands, has not been exhaustively investigated. We have now shown that incubation of purified neutrophils with hFbg induces a transient and rapid elevation of free intracellular Ca2+. This early intracellular signal is accompanied by changes in the expression of neutrophil activation markers, including enhancement of CD11b and CD66b, and down-regulation of FcγRIII. In addition, we have evaluated the effect of hFbg on two functional events related to expression and resolution of inflammation: cytotoxic capacity and rate of neutrophil apoptosis. We have found that activation of neutrophils by hFbg resulted in both enhancement of phagocytosis and Ab-dependent cellular cytotoxicity, and delay of apoptosis. We conclude that during inflammatory processes, soluble Fbg could influence neutrophil responses, increasing and prolonging their functional capacity.

Soluble Fibrinogen Modulates Neutrophil Functionality Through the Activation of an Extracellular Signal-Regulated Kinase-Dependent Pathway

“…However, exposure to sFbg or cytokines such as GM-CSF and IL-6 has been shown to delay apoptosis (7,54,55), thereby contributing to host defense or, under other circumstances, tissue injury. It has been previously reported that ERK MAPK pathway is involved in cell survival and preventing or delaying apoptosis (56 -58).…”

Tissue adhesives in ocular surgery

“…Fibrinogen has been determined to be involved in the acute inflammatory response phase, activating neutrophil markers that cause an increase in phagocytosis, cellular cytotoxicity and apoptosis delay [139]. Therefore, reduced amounts of fibrinogen for surgical procedures are recommended to prevent additional inflammatory reactions.…”

A role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling in the human neutrophil

“…Because adherent neutrophils respond differently to TNF-␣ than those in suspension, it is possible that input from integrin-activated signaling may have a critical role in regulating TNF-␣-mediated antiapoptotic signaling. Indeed, different extra-cellular matrix proteins have disparate effects on neutrophil spontaneous apoptosis and may have an important role in regulating TNF-␣ antiapoptotic and proapoptotic signaling (47,56).…”