Dissecting the intrinsic role of SLC4A2 in the development of liver inflammation in a mouse model of PBC

/Abstract The SLC4A2 (or Anion Exchanger2, AE2) is a ubiquitous membrane transporter that mediates the sodium (Na+)- independent and electroneutral exchange of chloride (Cl−) and bicarbonate (HCO3−) ions, and participates in the regulation of intracellular pH (pHi). AE2-deficiency in humans has been linked with the development of Primary Biliary Cholangitis (PBC), which is a chronic cholestatic liver disease associated with autoimmune phenomena. Supporting these findings, mice with whole-body deletion of SLC4A2 develop a spontaneous and progressive autoimmune cholangitis that resembles the human PBC. However, the cell intrinsic requirement of SLC4A2 in immune cells and/or biliary epithelial cells and the mechanisms underlying the loss of tolerance against biliary epithelial cells in the absence of SLC4A2 are unknown. Here, we aim to dissect the role of SLC4A2 in the development of liver inflammation and autoimmune cholangitis using SLC4A2 conditional knockout (cKO) mice. To this end, we have generated tissue-specific SLC4A2-cKO in the liver (i.e., Slc4a2fl/flAlbCre+ mice) as well as in T cells (i.e., Slc4a2fl/flCd4Cre+ mice) to study the requirement of this membrane transporter in immune tolerance in the liver. We aim to: 1) characterize the immune cell composition in the liver and lymphoid organs of Slc4a2fl/flCd4Cre+, Slc4a2fl/flAlbCre+ mice and their control littermates, and ii) study the alterations that occur in T cells and liver cells in the absence of SLC4A2. Investigating the mechanisms underlying the autoimmune cholangitis and liver inflammation caused by SLC4A2 deficiency in mice will be an important step forward to better understand the etiopathogenesis of PBC and to the development of future therapeutic approaches to treat these patients. Project Number: 1R03AI196747-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Axel Concepcion Gonzalez | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $164,000 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 KUDS-S (04)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03AI19674701