Fibrinogen‐CD11b/CD18 interaction activates the NF‐κB pathway and delays apoptosis in human neutrophils

Abstract

The regulation of neutrophil half-life by members of the coagulation cascade is critical for the resolution of the inflammatory response. We have demonstrated that soluble fibrinogen (sFbg) delays human neutrophil (PMN) apoptosis through a mechanism that involves CD11b interactions, and phosphorylation of focal adhesion kinase (FAK) and extracellular signalregulated kinase 1/2 (ERK1/2). Since NF-‹ B is a key element in the regulation of apoptotic mechanisms in several immune cells, we investigated whether NF-‹ B is involved in the control of PMN survival by sFbg. We show that sFbg triggers inhibitor protein ‹ B (I ‹ B- § ) degradation and NF-‹ B activation. Furthermore, pharmacological inhibition of NF-‹ B abrogates sFbg effects on apoptosis. In addition, specific inhibition of MAPK ERK1/2 significantly reduces NF-‹ B translocation by sFbg, suggesting a relationship between ERK1/2 and NF-‹ B activation. Similar results are obtained when granulocytic-differentiated HL-60 cells are treated with sFbg, making this model highly attractive for integrin-induced gene expression studies. It can be concluded that NF-‹ B participates in the prevention of apoptosis induced by sFbg with the participation of MAPK ERK1/2. These results shed light on the molecular mechanisms that control human granulocyte apoptosis, and suggest that NF-‹ B regulation may be of benefit for the resolution of the inflammatory response.

Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway

“…In agreement with the capacity of fibrinogen to activate the NF-B pathway via engaging its receptor Mac-1 (Supplemental Fig. 3c; Sitrin et al 1998;Rubel et al 2003), treatment of primary macrophages with the NF-B inhibitor BAY11-7085 abrogated fibrinogen-induced proinflammatory cytokine production (Supplemental Fig. 3d).…”

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…CD11b/CD18 ligation and clustering mediate proinflammatory signaling in leukocytes, including synergistic potentiation of signaling by other receptors (23)(24)(25)(26)(27)(28)(29)(30)(31). Conversely, they have also been shown to negatively regulate signaling by TLRs, TNF receptors, and cytokine receptors (14,17,23,24,(32)(33)(34), which could suppress downstream IFN-I pathways.…”

Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense

“…Similarly, leukocyte engagement of immobilized fibrinogen in vitro through integrin [5][6][7] and nonintegrin 8,9 receptors is thought to support cell adhesion, migration, phagocytosis, nuclear factor-kB-mediated transcription, chemokine and cytokine elaboration, degranulation, and other processes. [9][10][11][12][13] Both fibrinogen and fibrin may have distinct and specialized properties that direct thrombotic and/or inflammatory events in vivo, but the precise form of the molecule driving fibrin(ogen)-associated events has not been established.…”