Mast Cell‐Derived Histamine Promotes Large Cholangiocyte Damage via H2 Histamine Receptor Signaling

The biliary tree contains both small and large ducts, that are surrounded by small and large cholangiocytes, respectively. Large cholangiocytes are more susceptible to damage, and proliferate following bile duct ligation (BDL). Further, we have shown that large cholangiocytes undergo senescence following cholestatic injury. Mast cells (MCs) infiltrate the liver following BDL, reside near large ducts, and secrete histamine that promotes biliary proliferation via cAMP/ERK signaling. Histamine signals through four histamine receptors (HRs), and H2HR is expressed by large cholangiocytes. The aim of our study was to identify the mechanism by which MC‐derived histamine promotes large cholangiocyte damage. 12 wk old male wild‐type (WT) and Kit W‐sh (MC‐deficient) mice were subjected to sham or BDL for 1 wk and selected WT and Kit W‐sh mice received one tail vein injection of cultured MCs 3 days prior to sacrifice. Large ductal mass was measured by CK‐19 staining and semi‐quantification, and q PCR for PCNA is isolated large cholangiocytes. Large cholangiocyte senescence was shown by immunofluorescence (IF) for p16 and p21 (co‐stained with CK‐19) in liver sections, and q PCR in isolated large cholangiocytes. In large ducts, we evaluated H2HR expression and cAMP and pERK, expression by IF. In vitro , MCs were treated with control or the l‐histidine decarboxylase (HDC) inhibitor (3 mM, a‐methyl‐dl‐histidine (a‐Me)) for 48 hrs. Supernatants from treated MCs were placed on cultured large cholangiocytes and evaluated for: (i) proliferation; (ii) senescence; (iii) H2HR expression; (iv) cAMP expression and activity; and (v) pERK expression . BDL WT mice had increased large (but not small) ductal mass, which was reversed in BDL Kit W‐sh mice. MC injection into WT and Kit W‐sh mice increased large duct mass. Similarly, large cholangiocyte senescence increased following MC injections and in BDL WT mice, but was reduced in BDL Kit W‐sh mice. MC injection and BDL WT mice had enhanced large cholangiocyte H2HR/cAMP/pERK expression; however, this was decreased in BDL Kit W‐sh mice. In vitro , large cholangiocytes treated with MC supernatants had increased (i) proliferation, (ii) senescence, and (iii) H2HR/cAMP/pERK signaling. However, these parameters were reduced in large cholangiocytes treated with supernatants from MCs treated with a‐Me. During cholestatic liver injury, MCs primarily induce large cholangiocyte damage and MC‐derived histamine promotes large cholangiocyte proliferation and senescence via H2HR/cAMP/pERK signaling. Inhibition of MC‐derived histamine or large cholangiocyte H2HR signaling may be therapeutic for patients with large ductal damage. Support or Funding Information VA Merit and NIH NIDDK R01 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .