Hepatic Ly6CLo Non-Classical Monocytes Have Increased Nr4a1 (Nur77) in Murine Biliary Atresia

Sarah Mohamedaly; Claire S Levy; Cathrine Korsholm; Anas Alkhani; Katherine Rosenberg; Judith F Ashouri; Amar Nijagal

doi:10.3390/jcm11185290

Hepatic Ly6C^Lo Non-Classical Monocytes Have Increased Nr4a1 (Nur77) in Murine Biliary Atresia

J Clin Med. 2022 Sep 8;11(18):5290. doi: 10.3390/jcm11185290.

Authors

Sarah Mohamedaly^{1

2}, Claire S Levy^{1

2}, Cathrine Korsholm³, Anas Alkhani^{1

2}, Katherine Rosenberg^{1

2}, Judith F Ashouri⁴, Amar Nijagal^{1

2

5

6}

Affiliations

¹ Department of Surgery, University of California, San Francisco, CA 94143, USA.
² Liver Center, University of California, San Francisco, CA 94143, USA.
³ Department of Comparative Pediatrics and Nutrition, University of Copenhagen, 1870 Frederiksberg, Denmark.
⁴ Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, CA 94143, USA.
⁵ The Pediatric Liver Center, UCSF Benioff Children's Hospital, San Francisco, CA 94143, USA.
⁶ Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, CA 94143, USA.

Abstract

Biliary atresia (BA) is a rapidly progressive perinatal inflammatory disease, resulting in liver failure. Hepatic Ly6CLo non-classical monocytes promote the resolution of perinatal liver inflammation during rhesus rotavirus-mediated (RRV) BA in mice. In this study, we aim to investigate the effects of inflammation on the transcription factor Nr4a1, a known regulator of non-classical monocytes. Nr4a1-GFP reporter mice were injected with PBS for control or RRV within 24 h of delivery to induce perinatal liver inflammation. GFP expression on myeloid immune populations in the liver and bone marrow (BM) was quantified 3 and 14 days after injection using flow cytometry. Statistical significance was determined using a student’s t-test and ANOVA, with a p-value < 0.05 for significance. Our results demonstrate that non-classical monocytes in the neonatal liver exhibit the highest mean fluorescence intensity (MFI) of Nr4a1 (Ly6CLo MFI 6344 vs. neutrophils 3611 p < 0.001; macrophages 2782; p < 0.001; and Ly6CHi classical monocytes 4485; p < 0.0002). During inflammation, hepatic Ly6CLo non-classical monocytes showed a significant increase in Nr4a1 expression intensity from 6344 to 7600 (p = 0.012), while Nr4a1 expression remained unchanged on the other myeloid populations. These findings highlight the potential of using Nr4a1 as a regulator of neonatal hepatic Ly6CLo non-classical monocytes to mitigate perinatal liver inflammation.

Keywords: biliary atresia; cholangiopathy; innate immune system; monocytes; perinatal liver inflammation.

Abstract

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