8-fold), Hmox1 (heme oxygenase 1; 3.4-fold), Folr2 (folate receptor-2; 2.6-fold), Prdx6 (periredoxin-6; 2.5-fold), selleck inhibitor and Spsb4

(SPRY domain and SOCS box containing protein 4; 2.5-fold) (Fig. 5) [43-49]. If Arg1+ cells do have the potential for neuroprotection following TBI, this may be overwhelmed by Arg1− cells, which are greater in number and are less transient. Our findings demonstrate a heterogeneous macrophage response to TBI that changes over time. Expression profiling of Arg1+ and Arg1− macrophage subpopulations demonstrate that they do not exemplify previously described in vitro derived macrophage subsets [17]. They also differ from macrophages that accumulate in skin wound macrophages [50]. Skin wound macrophages, such as TBI-induced Arg1+ cells, both express Arg1 and Mrc1. However, skin macrophages additionally upregulated Clec7a, and do not express Nos2, features that distinguish them from TBI-induced Arg1+ cells. find more It may not be surprising that the macrophage response to TBI differs from macrophage polarization induced in vitro

or in other organs and other in vivo conditions. It is likely that macrophages can assemble their functions and products in a variety of combinations with great diversity. Our findings do demonstrate the heterogeneity of the macrophage response to TBI and they suggest that Arg1 should not in isolation be used as a marker for M2 cells. In this regard, Arg1 expression can be induced by pathways independent of IL-4/STAT6 [51]. Although we were able to identify macrophage subsets by using Arg1 as a marker in YARG mice, we could not detect robust expression of IL-12p40 by flow cytometry on days 1, 4, 7, or 14 in any macrophages or microglia by using Yet40 17-DMAG (Alvespimycin) HCl mice or by gene expression profiling comparing Arg1+ and Arg1− macrophages, as assessed by gene profiling. This suggests that IL-12p40 may not be a major effector cytokine promoted by brain macrophages or microglia in TBI, and that early in TBI, IL-12p40 is not inversely proportional to Arg1 expression.

Other M1 genes are detected, however, both in Arg1+ and Arg1− cells. Thus, the use of a single marker to define M1 and M2 cells in TBI appears not to be sufficient, and the functional consequences of the Arg1+ and Arg1− cell populations on the course of TBI remain unknown. Our findings do not exclude the possibility that there are more than two subsets of responding macrophages, and this is clearly supported by the bimodal expression of MHCII in Arg1− macrophages. Also, despite the extensive differences in gene expression between these cell subsets, particularly, in the expression of chemokines, it is also possible that Arg1+ and Arg1− macrophages may have a shared lineage and/or be partially polarized and that one subtype could become or becoming the other.