Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism

Abstract

The role of neurokinin-1 receptors (NK1R) in the interaction between mast cells and substance P (SP) in bladder inflammation was determined. Mast cell-deficient Kit(W)/Kit(W-v), congenic normal (+/+), and Kit(W)/Kit(W-v) mice that were reconstituted with bone marrow cells isolated from NK1R(-/-) mice were challenged by instillation of SP, antigen, or saline into the urinary bladder. Twenty-four hours after challenge, the bladders were prepared for morphological assessment and gene expression. SP-induced bladder inflammation was mast cell dependent and did not require NK1R expression on the mast cell. Cluster analysis identified functionally significant genes that were dependent on the presence of mast cells for their upregulation regardless of stimulus. Those include serine protein inhibitor 2.2, maspin, mitogen- and stress-activated protein kinase 2, and macrophage colony-stimulating factor 1. Our findings demonstrate that while mast cells are essential for both antigen- and SP-induced bladder inflammation, there are common genes and unique genes expressed in each type of inflammatory reaction. When combined with unique animal models, gene array analysis provides a useful approach for identifying and characterizing pathways involved in bladder inflammation.

Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity

“…48 Under our conditions, the proinflammatory tachykinins induced their antiapoptotic effects on BMDCs at physiological concentrations, and this function was abrogated completely by the presence of NK1R antagonists or in BMDCs generated from NK1R Ϫ/ϪKO mice, demonstrating that the effect of the tachykinins on DC survival was mediated by NK1R binding. Moreover, our data suggest that antagonistic blockade of the NK1R does not exert apoptosis per se, but prevents from NK1R agonistic apoptotic rescue by competing for NK1R binding.…”

“…In addition, at very high concentrations, SP and HK-1 bind other neuropeptide receptors 47 or exert effects independently of receptor ligation. 48 Therefore, we investigated whether SP and HK-1, similar to SarSP, induce antiapoptotic effects on BMDCs and whether the apoptotic cell rescue induced by SarSP is mediated through NK1R signaling.…”

“…In addition, at very high concentrations, SP and HK-1 bind other neuropeptide receptors 47 or exert effects independently of receptor ligation. 48 Therefore, we investigated whether SP and HK-1, similar to SarSP, induce antiapoptotic effects on BMDCs and whether the apoptotic cell rescue induced by SarSP is mediated through NK1R signaling.SP, HK-1, and SarSP exerted similar antiapoptotic effects on BMDCs at their physiological concentration (10 Ϫ9 mol/L; P Ͻ .001), and a higher concentration (10 Ϫ5 mol/L) did not enhance this effect (P Ͼ .05; Figure 3A). The antiapoptotic effect of SarSP was mediated by NK1R binding, as demonstrated by the lack of apoptotic rescue by SarSP, in NK1R blockade assays of BMDCs pretreated with the selective NK1R antagonist WIN-51708 (P Ͻ .001) or in BMDCs generated from B6 NK1R Ϫ/ϪKO mice (P Ͻ .001; Figure 3B,C, respectively).…”

Translocation of Dynorphin Neuropeptides across the Plasma Membrane

“…Several actions of neuropeptides such as substance P and dynorphin A (Dyn A) are not mediated through their cognate receptors (17)(18)(19)(20). The proinflammatory actions of substance P, including stimulation of release of vasoactive and inflammatory compounds from peritoneal mast cells, involve a receptorindependent mechanism (21). This mechanism is apparently based on direct interaction of substance P with the ␣ subunit of heterotrimeric G proteins, following the peptide translocation across the plasma membrane (22).…”

Inflammation and Chronic Pelvic Pain: A Biological Trigger for Depression in Women?

“…MC activation may, in turn, induce bladder inflammation by acting on the urothelium. While histamine has been postulated to modulate pelvic pain, TNF-α seems to be involved in pathophysiological changes in the urinary bladder, including inflammatory changes [40,44].…”