The Neutrophil-Activating Protein of Helicobacter pylori Crosses Endothelia to Promote Neutrophil Adhesion In Vivo

Abstract

Helicobacter pylori induces an acute inflammatory response followed by a chronic infection of the human gastric mucosa characterized by infiltration of neutrophils/polymorphonuclear cells (PMNs) and mononuclear cells. The H. pylori neutrophil-activating protein (HP-NAP) activates PMNs, monocytes, and mast cells, and promotes PMN adherence to the endothelium in vitro. By using intravital microscopy analysis of rat mesenteric venules exposed to HP-NAP, we demonstrated, for the first time in vivo, that HP-NAP efficiently crosses the endothelium and promotes a rapid PMN adhesion. This HP-NAP-induced adhesion depends on the acquisition of a high affinity state of β2 integrin on the plasma membrane of PMNs, and this conformational change requires a functional p38 MAPK. We also show that HP-NAP stimulates human PMNs to synthesize and release a number of chemokines, including CXCL8, CCL3, and CCL4. Collectively, these data strongly support a central role for HP-NAP in the inflammation process in vivo: indeed, HP-NAP not only recruits leukocytes from the vascular lumen, but also stimulates them to produce messengers that may contribute to the maintenance of the flogosis associated with the H. pylori infection.

Vector-Encoded Helicobacter pylori Neutrophil-Activating Protein Promotes Maturation of Dendritic Cells with Th1 Polarization and Improved Migration

“…HP-NAP also induces a Th1-polarized immune response by stimulating the secretion of IL-12 and IL-23 (12), and also other proinflammatory cytokines such as TNF-a and IL-8 (13). Most studies on HP-NAP have investigated its role on innate immunity (10,(14)(15)(16). But, to act as an anticancer agent, it needs to induce a potent and specific adaptive immune response.…”

Detection and evaluation of antibodies against neutrophil-activating protein of Helicobacter pylori in patients with gastric cancer

“…H pylori colonization is followed by infiltration of neutrophils, macrophages and lymphocytes in gastric mucosa. The degree of mucosal damag e is closely associated with the extent of neutrophil infiltration [2][3][4] . Multiple bacterial virulence factors, such as vacA, cagA and lipopolysaccharide (LPS), can modulate H pylori-induced inflammation.…”

The immune modulating activity of the Helicobacter pylori HP-NAP: Friend or foe?

“…Moreover, it was not considered that in vivo the under-flow conditions may bias the effects observed in vitro. The first in vivo evidence that HP-NAP promotes leukocyte adhesion to the endothelium and the subsequent extravasation was obtained by applying intravital microscopy analysis to rat mesenteric venules topically exposed to HP-NAP (Polenghi et al, 2007). The same study showed that HP-NAP is effectively transported across the endothelium via intracellular route and a proportion of the protein remains bound to the endothelium after transcytosis, similarly to what was reported for the chemokine CXCL8 (Middleton et al, 1997).…”

“…b2 Integrins, which are crucial for the tight adhesion of leukocytes to the endothelium before extravasation, need also to be activated to acquire their ligandbinding capacity. Again HP-NAP shows a role since it induces a conformational change of b2 integrins, resulting in an increased affinity for the endothelial partner (Polenghi et al, 2007). Collectively these data suggest that HP-NAP, via its direct intervention, has a crucial role in recruiting leukocytes towards the infected area and therefore, in triggering the inflammation process.…”

“…Thus, HP-NAP, both alone and together with other host-derived factors, triggers in vivo the PMN accumulation within the tissue, evoking the adhesive properties of PMN and endothelium. In addition, considering that recruited PMN release cytokines and chemokines and that, under HP-NAP stimulation, they release TNF-a, CXCL8, CCL3 and CCL4, PMN may contribute to the generation of the condition required for the recruitment of additional neutrophils, monocytes and lymphocytes (Polenghi et al, 2007). Although it is undoubted that HP-NAP plays a major role in PMN recruitment and activation, other bacterial factors are also important (Unemo et al, 2005).…”