Monocytes can be subdivided into two ontologically related but functionally distinct subsets, namely classical (CM) and non-classical monocytes (NCM). While CM have been actively studied in inflammation and cancer for decades, only recently we started gaining insights regarding the role of NCM in disease pathogenesis. CM, after staying in the circulation for several days, can undergo apoptosis or differentiate into NCM. Steady state NCM “patrol” the vasculature via a mechanism that requires the fractalkine receptor CX3CR1, engulfing apoptotic endothelial cells and sensing danger signals coming from the tissue [1]. Our understanding of the functions of NCM was greatly enhanced by the recognition that the orphan nuclear receptor NR4A1 is necessary for the differentiation of CM into NCM [2]. Global Nr4a1 knockout mice, which lack NCM, can, therefore, be used to determine whether they are causally linked to disease pathogenesis.

We recently used Nr4a1-/-mice in a model of allogeneic lung transplantation to demonstrate a role for NCM in the recruitment of neutrophils. Specifically we found that NCM, anatomically located within the pulmonary vasculature, are retained in human and murine donor lungs at the time of transplantation [3, 4]. Transplantation of lungs from Nr4a1-/-mice into wildtype recipients was associated with a marked reduction in neutrophil migration into the allograft following reperfusion, which was rescued by the adoptive transfer of wild-type NCM into Nr4a1-/-donor lungs. Similarly, pharmacologically depleting NCM in the donor lungs prior to the transplantation with liposomal-clodronate reduced neutrophil trafficking. Using transcriptomic profiling and genetic murine knockouts, we showed that the NCM produced neutrophil chemoattractants including chemokine (CXC motif) ligand 2 (CXCL2) in a toll receptor dependent manner. Our findings bolster reports from other investigators demonstrating that depletion of NCM can ameliorate tissue injury in other models including arthritis, traumatic brain injury, and acute glomerulitis. A role for NCM has also been implicated in the pathogenesis of diseases such as neuromyelitis optica, primary biliary cirrhosis, atherosclerosis, vascular inflammation, coronary artery disease and cardiac failure. Contrastingly, reduced levels of NCM have been associated with increased susceptibility to Ebola virus. There is also growing evidence implicating a role for NCM in cancer progression. Hanna et al. reported that