The Critical Role of Chemokine (C-C Motif) Receptor 2-Positive Monocytes in Autoimmune Cholangitis

Frontiers in Immunology
Debby ReuveniEhud Zigmond

Abstract

The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6Chi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in...Continue Reading

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Citations

Jun 11, 2019·Frontiers in Immunology·Wen-Tao MaDe-Kun Chen
May 10, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Da ChengXin Ni

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
ELISA
flows cytometry
Flow cytometry
PCR

Clinical Trials Mentioned

NCT03028740

Software Mentioned

Flow Jo

Related Concepts

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