Contents lists available at ScienceDirect Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm Research paper Leukotriene receptor expression in mast cells is affected by their agonists Justyna Agier a,1 , Sylwia Różalska b,1 , Karolina Wódz a , Ewa Brzezińska-Błaszczyk a, ⁎ a Department of Experimental Immunology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland b Department of Industrial Microbiology and Biotechnology, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland ARTICLE INFO Keywords: Mast cells Leukotriene receptors cysLTs LTB 4 Inflammation ABSTRACT The effects of LTs are mediated by GPCRs: cysLTs interact with CYSLTR1, CYSLTR2, or GPR17, and LTB 4 acts via BLT1R or BLT2R. Data relating to the presence of these receptors in mature tissue mast cells are not entirely known. By confocal microscopy with image analyses and flow cytometry, we established that native rat mast cells isolated from peritoneal cavity constitutively express all studied receptors. Moreover, we clearly documented that LTs by themselves can influence their own receptor expression. Low concentrations of LTs induce translocation of LT receptors from cell interior to plasma membrane, which can lead to increased mast cell responsiveness to LT stimulation. High concentrations of LTs cause internalization and, in consequence, reduction in the number of receptors on the cell surface, and it may result in desensitization of mast cells to subsequent LT stimulation. These observations may imply a physiological feedback mechanism regulating mast cell sensitivity to LT activation within tissues. 1. Introduction Leukotrienes (LTs), both LTB 4 and cysLTs, namely LTC 4 , LTD 4, and LTE 4 , are the family of lipid mediators derived from lipoxygenase pathway of the arachidonic acid (AA) metabolism. The production of LTs requires the reversible translocation of 5-lipoxygenase (5-LO) from the nucleoplasm or the cytosol to the perinuclear region. This enzyme, acting in concert with 5-lipoxygenase-activating peptide (FLAP), con- verts AA into 5 hydroperoxyeicosatetraenoic acid (5-HPETE), and next into LTA 4 . The unstable LTA 4 can be converted into either LTB 4 or LTC 4 , and the latter is metabolized to LTD 4 and LTE 4 [1–4]. LTs are synthesized by cells of the innate immune system in response to different immune and inflammatory stimuli. CysLTs are generated by various types of leukocytes, including eosinophils, basophils, mast cells, and macrophages, while LTB 4 is produced mainly by neutrophils, monocytes, and mast cells. It is noteworthy that LTs can also be produced through transcellular biosynthesis. Such transcellular path- way of LT synthesis has been described for macrophages, mast cells, monocytes, airway epithelial cells, kidney-derived endothelial cells, chondrocytes, and keratinocytes [5,6]. It has been well established that LTs exert pleiotropic effects and play an important role in the development of inflammation, as they stimulate different cells to the production of proinflammatory mediators and cytokines, promote cell adhesion to the vascular epithelium, and have the potency to recruit proinflammatory cells to the site of inflammation [1,2,4]. The biological effects of LTs are mediated by GPCRs. The cysLTs interact with specific cysLT receptors, namely CYSLTR1, CYSLTR2, and GPR17 [1,2,7]. Recent findings imply there is one more cysLT receptor specific for LTE 4 , namely GPR99 [8,9]. LTB 4 acts through two receptors, BLT1R and BLT2R, with high- and low-affinity to the ligand, respectively [3]. It should be stressed that cellular distribution of LT receptors is varied. CYSLTR1 is widely expressed by peripheral leukocytes, monocytes, macrophages, Th2 lymphocytes, B cells, but is also present in various types of structural cells. In addition to granulocytes and macrophages, expression of CYSLTR2 was found in cardiac Purkinje fiber cells, cardiac and vascular smooth muscles, endothelium and epithelium, adrenal chromaffin cells or brain cells [1,2]. The GPR17 is primarily expressed in the central nervous system, in particular on oligodendrocyte precursor cells, and in the kidney and heart [7]. The BLT1R expression has been reported predominantly in activated leukocytes, while BLT2R seems to be more ubiquitous, with the highest level in lymphocytes and hepatocytes [3]. Mast cells are long-lived resident connective tissue cells distributed throughout the body, and are especially numerous beneath the subepithelial layers of the skin, in the respiratory system, in the gastrointestinal and genitourinary tracts, and adjacent to blood vessels and nerves. These cells are a potent source of diverse mediators such as cytoplasmic granule-associated preformed mediators (e.g. histamine, proteases, proteoglycans, metalloproteinases), de novo generated and secreted arachidonic acid metabolites (i.e. LTs, prostaglandins (PGs), http://dx.doi.org/10.1016/j.cellimm.2017.04.010 Received 31 January 2017; Received in revised form 14 April 2017; Accepted 28 April 2017 ⁎ Corresponding author. 1 The two are co-authors. E-mail address: ewab@csk.umed.lodz.pl (E. Brzezińska-Błaszczyk). Cellular Immunology xxx (xxxx) xxx–xxx 0008-8749/ © 2017 Elsevier Inc. All rights reserved. Please cite this article as: Agier, J., Cellular Immunology (2017), http://dx.doi.org/10.1016/j.cellimm.2017.04.010