**8.2 Tie2-expressing macrophages**

Tie2 has been shown to play an important role in a subset of monocyte/macrophages known as Tie2-expressing monocytes or macrophages (TEMs). TEMs have been most studied in the setting of tumorigenesis and have been found to promote tumor development through a variety of mechanisms. In addition to potentiating overall tumor growth and metastasis, TEMs have been demonstrated to directly promote tumor angiogenesis [74]. Other research has shown that TEMs not only promote tumorigenesis but are necessary for tumor angiogenesis and tumor recurrence following chemotherapy [75]. Several mechanisms have been proposed as effectors of this process. The interaction of Angpt2 with Tie2 in TEMs has been implicated in the pro-angiogenic effect of TEMs as well as in metastasis. One study found that inhibition of Angpt2 blocked the pro-angiogenic function of TEMs in tumors, and another study suggested that inhibition of Angpt2 could help to limit metastasis [59]. Tumor-associated expression of Angpt2 has also been shown to increase expression of pro-angiogenic factors in TEMs [76]. In addition, TEMs in tumors display increased expression of the anti-inflammatory cytokine IL-10. Stimulation of these cells by Angpt2 can work through IL-10 to influence activity of T cells by decreasing T-cell proliferation and increasing regulatory T cells for an overall immunosuppressive effect [77]. Angpt1-Tie2 interaction may also influence tumor development. TEMs are known to express Angpt1 [78], indicating that they may be able to activate Tie2 through autocrine signaling. Angpt1 expression in tumor-infiltrating TEMs has been suggested as a mechanism of increasing tumor angiogenesis through interaction with

**27**

*Peripheral Immune Response Following Traumatic Brain Injury*

endothelial cells [78]. While both Angpt1 and Angpt2 may influence the tumorpromoting activity of TEMs, studies agree that the protumorigenic activity of these cells is under control of Tie2/Angiopoietin signaling. This discovery has established the Tie2/Angiopoietin signaling axis as a target of interest in tumor therapeutic research. Several treatments aimed at blocking Tie2/Angiopoietin signaling are currently in development, with three Tie2/Angiopoietin inhibitors currently in clinical trials as cancer therapeutics [79]. No trials are currently

The origin and M1/2 polarization status of TEMS is currently under active investigation. Some studies have found that these cells seem to be polarized toward the M2 phenotype [80]. TEMs have been shown to display increased expression of arginase 1 (Arg1) and scavenger receptors accompanied by decreased expression of pro-inflammatory and anti-angiogenic mediators compared to tumor-associated macrophages that lack Tie2 expression. This expression pattern is consistent with an M2 polarization state [78]. In addition, TEMs exert an anti-inflammatory effect in the context of tumorigenesis. These cells release IL-10 and VEGF, decrease T-cell proliferation, inhibit antigen presentation by dendritic cells, and promote T-cell conversion to regulatory T cells [80]. However, TEMs may also play important roles in a variety of disease settings aside from tumorigenesis. Specifically, many studies have implicated TEMs as key regulators

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

*DOI: http://dx.doi.org/10.5772/intechopen.93597*

underway for brain injury.

of inflammation.

**9. TEMs in inflammation**

#### *Peripheral Immune Response Following Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.93597*

endothelial cells [78]. While both Angpt1 and Angpt2 may influence the tumorpromoting activity of TEMs, studies agree that the protumorigenic activity of these cells is under control of Tie2/Angiopoietin signaling. This discovery has established the Tie2/Angiopoietin signaling axis as a target of interest in tumor therapeutic research. Several treatments aimed at blocking Tie2/Angiopoietin signaling are currently in development, with three Tie2/Angiopoietin inhibitors currently in clinical trials as cancer therapeutics [79]. No trials are currently underway for brain injury.

The origin and M1/2 polarization status of TEMS is currently under active investigation. Some studies have found that these cells seem to be polarized toward the M2 phenotype [80]. TEMs have been shown to display increased expression of arginase 1 (Arg1) and scavenger receptors accompanied by decreased expression of pro-inflammatory and anti-angiogenic mediators compared to tumor-associated macrophages that lack Tie2 expression. This expression pattern is consistent with an M2 polarization state [78]. In addition, TEMs exert an anti-inflammatory effect in the context of tumorigenesis. These cells release IL-10 and VEGF, decrease T-cell proliferation, inhibit antigen presentation by dendritic cells, and promote T-cell conversion to regulatory T cells [80]. However, TEMs may also play important roles in a variety of disease settings aside from tumorigenesis. Specifically, many studies have implicated TEMs as key regulators of inflammation.
