Unidirectional heterologous receptor desensitization between both the fMLP and C5a receptor and the IL-8 receptor

Abstract

During inflammation neutrophils receive multiple signals that are integrated, allowing a single modified response. One mechanism for this discrimination is receptor desensitization, a process whereby ligand-receptor binding is disassociated from cell activation. We examined the effect of heterologous receptor desensitization on neutrophil chemotaxis, calcium mobilization, and arachidonic acid production, using interleukin-8 (IL-8), C5a, and N-formyl-methionyl-leucyl-phenylalanine (fMLP). We observed reciprocal inhibition with respect to chemotaxis. We demonstrated that homologous desensitization, with respect to the mobilization of intracellular calcium stores, lasted approximately 15 min. Heterologous desensitization between the fMLP receptor and the C5a receptor was reciprocal; either stimulant would diminish the cells' response to stimulation by the other for approximately 3-5 min. However, we observed a unidirectional heterologous desensitization of the IL-8 receptor by both the fMLP and the C5a receptor. This unidirectional heterologous desensitization was observed with respect to both calcium mobilization and arachidonic acid production (i.e., prestimulation of the IL-8 receptor had no effect on subsequent stimulation by either fMLP or C5a).

The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2

“…Activation of neutrophils through FPRs induces a variety of pro-inflammatory and antibacterial effector mechanisms including production of ROS, and release of antimicrobial peptides (AMPs) and hydrolytic enzymes from intracellular granules [20]. Furthermore, FPRs regulate the inflammatory reactions in neutrophils by modulating signaling through many other receptors in a process termed receptor cross-talk [21][22][23][24]. The role of FPRs in regulation of inflammation is highlighted by their suggested involvement in both systemic [25] and local [26][27][28] inflammatory responses.…”

Chemokine immunobiology in HIV-1 pathogenesis

“…For example, asymmetric heterologous desensitization of certain peptide chemoattractant receptors has been reported [172,173] and we have recently observed that MCP-1 signaling through CCR2b can desensitize subsequent signaling by cognate ligands through the major HIV-1 coreceptors, CCR5 and CXCR4 [85]. Therefore, studies looking at the effect of chemokine secretion on HIV-1 replication or infection may have to be expanded to include non-cognate ligands (like MCP-1), which can potentially affect the expression and/or function of cognate coreceptors.…”

Inhibition of neutrophil migration in mice by mouse formyl peptide receptors 1 and 2 dual agonist: indication of cross-desensitization in vivo

“…Indeed, the stimulation of FPR1 with fMLF desensitized not only FPR1 but also C5aR and chemokine (C-X-C motif) receptor 2 (CXCR2), and inhibited neutrophil responses, such as calcium mobilization and chemotaxis, which are induced by C5a or IL-8. [13][14][15][16][17] It has also been reported that fMLF induces the internalization of CXCR2 from the cell surface as a result of cross-desensitization. 17 C5a and IL-8 can also cross-desensitize FPR1, but there is a hierarchy in the ability to induce cross-desensitization among chemoattractants, with a rank order of fMLF > C5a > IL-8.…”

“…tion has previously been demonstrated only under in vitro conditions. Although fMLF-induced cross-desensitization in vitro has been well documented, [13][14][15][16][17] in most cases it has been reported that the administration of fMLF in vivo induces typical effects of chemoattractants on neutrophils, such as neutrophil infiltration into the airway induced by the inhalation of fMLF [22][23][24] and transient neutropenia induced by the intravenous administration of fMLF. 25,26 Among these studies, only Ley et al 25 reported the possibility of an inhibitory effect of fMLF on neutrophil migration towards chemoattractants.…”

“…These results are consistent with observations in studies describing cross-desensitization in human cells induced by fMLF. [13][14][15][16][17] In calcium mobilization assays, we showed that the inhibitory effect of Cpd43 on KC-and LTB 4 -induced calcium mobilization was stronger than that on mC5a-induced calcium mobilization. These results are consistent with the hierarchy of the ability to induce cross-desensitization (fMLF > C5a > IL-8), 14 which means that the C5a-induced signal is more resistant to the induction of cross-desensitization.…”