Lack of neurokinin-1 receptor expression affects tissue mast cell numbers but not their spatial relationship with nerves

Abstract

-A spatial association between mast cells and nerves has been described in both the gastrointestinal and genitourinary tracts. However, the factors that influence the anatomic relationship between mast cells and nerves have not been completely defined. It has been suggested that the high-affinity receptor for substance P [neurokinin-1 (NK1)] might modulate this interaction. We therefore assessed mast cell-nerve relationships in tissues isolated from wild-type and NK1 receptor knockout (NK1 Ϫ/Ϫ ) mice. We now report that, in the complete absence of NK1 receptor expression, there is a significant increase in the number of mast cells without a change in the anatomic relationship between mast cell and nerves in stomach and bladder tissues at the light microscopic level. We next determined whether transplanted mast cells would maintain their spatial distribution, number, and contact with nerve elements. For this purpose, mast cell-deficient Kit W /Kit WϪv mice were reconstituted with wild-type or NK1 Ϫ/Ϫ bone marrow. No differences in mast cell-nerve contact were observed. These results suggest that NK1 receptor expression is important in the regulation of the number of mast cells but is not important in the interaction between mast cells and nerves. Furthermore, the interaction between mast cells and nerves is not mediated through NK1 receptor expression on the mast cell. Further studies are needed to determine the molecular pathway involved in mast cell migration and interaction with nerve elements, but the model of reconstitution of Kit W /Kit WϪv mice with mast cells derived from different genetically engineered mice is a useful approach to further explore these mechanisms. cystitis; substance P; disease animal model MAST CELLS ARE NORMALLY DISTRIBUTED throughout mucosal surfaces in proximity to blood vessels (21), lymphatics (56), peripheral nerves (22), and epithelial cells. This pattern of distribution facilitates the exposure of mast cells to stimuli, such as soluble protein, antigens (26), or neuropeptides (10), that can induce activation. Furthermore, it places the mast cell at the interface of potentially critical host-pathogen interactions (6, 28) and in turn makes their cell products available to a variety of cell types in the microenvironment, including sensory and autonomic nerves (22,47,48) and smooth muscle cells (16 -18).Spatial associations in biological systems are often indicative of functional interactions. In this context, nerve-mast cell interaction has been described in the skin and in the gastrointestinal (GI) and urinary tracts (4, 30, 33, 50). Early studies elegantly described the nonrandom spatial association of mast cells with nerves in a variety of tissues in which actual membrane-membrane contacts occur (11,22,32,44,47,48). In the GI tract, several studies have suggested that mast cell-nerve interaction has an important homeostatic role in the regulation of gut physiology as well pathophysiology (57). Studies that have utilized mast cell-deficient Kit W /Kit WϪv (Kit) mice have provide...

A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

“…In allergic airway inflammation and cystitis induced by antigen sensitization and challenge, NK1RϪ/Ϫ mice were protected from edema and neutrophil influx (53,62). NK1RϪ/Ϫ animals exhibited significantly increased mast cell numbers following sensitization, and histological evidence of degranulation was apparent following antigen challenge (17,53). Thus substance P-NK1R interactions contribute to the pathophysiology of allergic inflammatory reactions.…”

“…For some analyses, results from room air-exposed wild-type and NK1RϪ/Ϫ mice were combined in the interest of conserving animals. This modified control is justified by the observation that baseline parameters of inflammation in this mouse line have never been different from those of wild-type animals (6,8,11,17,23,52,53,62).…”

Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation

“…Evidence for a role of mast cells in cystitis was reviewed recently [5] and includes the presence of mast cells containing tryptase in the bladder [6] and urine of IC patients [6,7], and that mast cell counts in IC patients are one of the few features significantly associated with night-time frequency of urination [8]. We have previously presented direct evidence indicating a key role for mast cells and their products in bladder inflammation [9-11], and others emphasized the role of mast cell products in bladder disorders [12-14]. …”

Regulatory network of inflammation downstream of proteinase-activated receptors

“…In particular, neurogenic bladder inflammation involves the participation of mast cells and sensory nerves. We previously presented evidence indicating a key role for mast cells and their products in bladder inflammation [5-7]. As a consequence of inflammation, products of mast cell degranulation such as tryptase can be found in the urine of both bladder cancer and cystitis patients [8].…”