*Purpose: Ischemia reperfusion injury (IRI) is well-appreciated as a significant clinical concern for recipients of liver transplantation, yet there are still no diagnostic or therapeutic strategies available to alleviate its significant influence on both short and long term allograft and patient survival. We and others have previously identified myeloid cells as key players in the sustained tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities have been difficult to determine as overall numbers of these cells are often similar in range between individuals regardless of their IRI status. Thus, there is a fundamental need for understanding the molecular pathways associated with myeloid cells present in either IRI- or IRI+ recipients of liver transplants.

*Methods: We performed RNA-seq on 80 longitudinal pre- and post-reperfusion biopsies from 40 human liver transplant recipients (23 IRI+, 17 IRI-). To further characterize myeloid involvement, we used transcriptional profiling and computational approaches to identify specific gene co-expression network modules which correlated with numbers of LYSO+ myeloid cells, MPO+ neutrophils and CD68+ monocytes/macrophages as determined by immunohistochemistry on sequential sections from the same patient biopsies.

*Results: The global molecular map generated by this unique computational approach revealed markers of early myeloid activation in the pre-reperfusion samples of IRI+ recipients coupled with subsequent lymphocyte activation at the post-reperfusion timepoint, which identified transcriptional programs associated with the transition to adaptive immunity. IRI- recipients were found to have a less inflammatory profile both pre- and post-reperfusion than samples from IRI+ recipients, with pre-reperfusion samples dominated by myeloid genes related to a response to injury, followed by regeneration or repair signaling at the post-reperfusion time point.

*Conclusions: Strategies to therapeutically target these myeloid-specific genes and related signaling pathways, as well as improve donor-recipient matching are urgently needed to limit IRI in the clinical setting of liver transplantation.

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