Reply

Authors


  • Potential conflict of interest: Nothing to report.

We thank Dr. French for his comments and questions about our study on the role of the ecto-nucleotidase CD73 in mouse liver Mallory-Denk body (MDB) formation.[1] CD73 is expressed in multiple tissues, including the lung, heart, brain, kidney, liver, and the immune system.[2] Although formation of extracellular adenosine is considered its primary function, CD73 also may act in a number of other ways independent of its enzymatic role.[3]

As Dr. French pointed out, our findings that CD73−/− mice are resistant to MDB formation is somewhat counterintuitive, given our initial observation that the MDB-susceptible mouse strain (C57BL/6J) is characterized by having lower CD73 mRNA and protein levels under basal conditions compared to the MDB-resistant C3H/He strain. However, we also showed that after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment there was a near complete loss of cell surface CD73 (AMPase) activity, but only a 60% decrease in overall CD73 activity (measured biochemically after tissue lysis). This observation, together with our findings of DDC-induced loss of plasma membrane CD73 in isolated hepatocytes, illustrates the complex nature of CD73 regulation in this model of liver injury. Therefore, the subcellular distribution (organellar versus plasma membrane) and regulation (such as glycosylation changes and enzymatic activity) of CD73 during hepatocellular injury are likely a more important determinant of hepatocyte injury than the overall CD73 expression levels.

Furthermore, the MDB resistance in CD73−/− mice also may be immune-related, given the known major role of CD73 in regulating inflammatory and immune responses.[4] For example, in absence of CD73 to catalyze the final and irreversible step in the conversion of extracellular adenosine triphosphate (ATP) to adenosine, the ATP levels in the vicinity of damaged and dying cells may significantly increase. This can accelerate the clearance of damaged cells by promoting phagocytosis by way of a number of mechanisms.[5] Altered purinergic signaling on other immune cell types, such as regulatory T cells,[6] also may alter the course of liver injury progression in CD73−/− mice.

In summary, resistance to MDB formation in CD73−/− mice likely is related to a number of hepatocyte-intrinsic and -extrinsic mechanisms. Generation of mice with targeted deletion of CD73 from specific cell types should help resolve many outstanding questions pertaining to the functions of this enzyme in the liver.

  • Natasha T. Snider, Ph.D.

  • M. Bishr Omary, M.D., Ph.D.

  • Department of Molecular & Integrative Physiology

  • University of Michigan Medical School

  • Ann Arbor, MI

Ancillary