**9. TEMs in inflammation**

An influential role of TEMs under inflammatory conditions remains under investigation. In the setting of inflammation, Tie2 expression may influence macrophage phenotype on the M1/2 continuum [45]. While TEMs have been shown to favor the M2 phenotype in the context of tumor infiltration, Tie2 expression has been demonstrated in monocytes polarized to both M1 and M2 phenotypes [60, 78]. Investigations of whether Tie2 expression in inflammatory disease correlates with M1 or M2 phenotype have shown conflicting results. One study showed Tie2 activation in synovial macrophages of human patients with autoimmune rheumatoid arthritis. In this study, Angpt2/Tie2 signaling interacted with TNF to up-regulate IL-6 and macrophage inflammatory protein 1α (MIP-1α), and antagonizing this pathway reduced synovial inflammation in a mouse model of disease [81]. Exogenous Angpt1 application to human monocyte cultures has been shown to up-regulate TNF and possibly regulate their polarization state [45]. Another study found that Angiopoietin binding works synergistically with TNF to drive expression of pro-inflammatory cytokines in human-cultured monocytes under several polarized conditions [60]. In contrast, previous studies showed anti-inflammatory effects of Angpt1 binding in TEMs and found that Angpt1 blocks LPS-induced TEM migration and ameliorates LPS-induced TNF expression via NF-ΚB [82]. Angpt2 has also been shown to augment immunosuppressive cytokines and T-reg chemokines expressed by TEMS *in vitro* [77]. These conflicting results suggest that Tie2 signaling may serve differential functions depending on acute and chronic conditions and may be dependent upon the activation state of the cells. Furthermore, the role of clustering and oligomerization of angiopoietin molecules on Tie2 binding and activation [83] raises the possibility that Tie2 may be differentially regulated under these conditions, although individual studies failed to confirm p-Tie2 states directly. Therefore, the role of Tie2 activation in the M1/M2 continuum remains unclear. While Tie2 signaling has been implicated in promoting injury-induced and tumor-promoting vascular health in numerous non-CNS models [59, 74, 75], its role

in regulating monocyte/macrophage polarization in CNS inflammation remains unexplored. Furthermore, limited data exist regarding novel pathways that may regulate Tie2 function in TBI-induced peripheral immune response.
