Virus-associated Inflammation Imprints an Inflammatory Profile on Long-lived Monocyte-derived Macrophages in the Human Liver

Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immunotolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of chronic hepatitis B (CHB) patients with active liver inflammation starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA sequencing mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and established a long-lived population. The iMacs retained their core transcriptional signature, consistent with trained immunity, resulting in a population of macrophages primed for inflammation potentially driving progressive liver disease. ### Competing Interest Statement D.M. is employed by Fluidigm Inc. S.C.K. is employed by and stockholder of Gilead Sciences Inc. D.C. was formerly employed by Gilead Sciences Inc. and is currently employed by Bristol Myers Squibb. J.J.F. receives research funding by Abbvie, Arbutus Biopharma, Gilead Sciences Inc., Janssen Pharmaceuticals, Eiger Biopharmaceuticals, and Enanta Pharmaceuticals; and reports compensation from consulting/scientific advising for Abbvie, Arbutus Biopharma, Gilead Sciences Inc., and GlaxoSmithKline. S.F. receives research funding by Gilead Sciences Inc.; and reports compensation from consulting/scientific advising for Gilead Sciences Inc., Abbvie, Janssen Pharmaceuticals, Assembly Biosciences. J.J.W. is employed by and stockholder of Gilead Sciences Inc. A.G. was formerly employed by and stockholder of Gilead Sciences Inc. H.L.A.J. receives research funding by Abbvie, Gilead Sciences Inc., GlaxoSmithKline, Janssen Pharmaceuticals, Roche, Vir Biotechnology; and reports compensation from consulting/scientific advising for ALIGOS Therapeutics, Antios Therapeutics, Arbutus Biopharma, Eiger Biopharmaceuticals, Gilead Sciences Inc., GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Roche, VBI Vaccines Inc., Vir Biotechnology, and Viroclinics Biosciences. A.J.G. receives research funding by Janssen Pharmaceuticals, GlaxoSmithKline, and Gilead Sciences Inc.; and reports compensation from consulting/scientific advising: Janssen Pharmaceuticals, Roche, GlaxoSmithKline, Vir Biotechnology, Finch Therapeutics, SQZ Biotech. The other authors declare no competing interests.