Histamine-Mediated Autocrine Regulation in Perilymphatic Mast Cells

Lymphatic vessels play a critical role in mounting a proper immune response by trafficking peripheral immune cells to draining lymph nodes. Mast cells (MCs) are well known for type I hypersensitivity reactions but little is known about their secretory regulation in the lymphatic niche. MCs, as innate sensor and effector cells, reside close to mesenteric lymphatic vessels (MLVs) and their activation and ability to release histamine influences the lymphatic microenvironment in a histamine-NF-B-dependent manner. Using surgically isolated rat mesenteric tissue segments, we tested the hypothesis that perilymphatic mesenteric MCs express histamine receptors (HR) that bind and respond to histamine that they release. Under various experimental conditions, including inflammatory stimulation by lipopolysaccharide (LPS), we measured histamine in mesenteric perilymphatic tissues, evaluated expression of histidine decarboxylase, the degree of MC degranulation, assessed the functional status of HRs in MCs, and evaluated the ability of histamine itself to induce MC activation. Finally, we evaluated the significance of MCs and histamine receptor 1 (H1R) and histamine receptor 2 (H2R) for MLV-directed trafficking of CD11b/c-positive cells during LPS-mediated acute tissue inflammation. Our data indicate the existence of a functionally active MC-histamine autocrine regulatory loop, the elements of which are crucially important for acute inflammation-induced trafficking of the CD11b/c-positive cells towards MLVs. Our data also suggest that this MC-histamine loop plays a key role in the innate and adaptive immune response as well. Current study along with previous evidence suggests the presence of an antagonistic relationship between H2R and H1R. Our demonstration of nuclear localization for H2R in different tissue types and cell lines in addition to the emerging evidence of Gprotein-coupled receptors as nuclear receptors led us to investigate the localization pattern for H2R in rat whole tissue segments as well as human lymphatic endothelial cells. We demonstrate histamine-dependent nuclear translocation kinetics of H2R as well as report that loss of function of H2R significantly attenuates such a translocation event. Altogether our results suggest that receptor-ligand complex formation is necessary for H2R nuclear translocation, which is known to be a key functional characteristic of type 1 nuclear receptor signaling event