INJURY-INDUCED GR-1+ MACROPHAGE EXPANSION AND ACTIVATION OCCURS INDEPENDENTLY OF CD4 T-CELL INFLUENCE

Burn injury initiates an enhanced inflammatory condition referred to as the systemic inflammatory response syndrome or the two-hit response phenotype. Prior reports indicated that macrophages respond to injury and demonstrate a heightened reactivity to Toll-like receptor stimulation. Since we and others observed a significant increase in splenic GR-1(+) F4/80(+) CD11b(+) macrophages in burn-injured mice, we wished to test if these macrophages might be the primary macrophage subset that shows heightened LPS reactivity. We report here that burn injury promoted higher level TNF-alpha expression in GR-1(+), but not GR-1(-) macrophages, after LPS activation both in vivo and ex vivo. We next tested whether CD4(+) T cells, which are known to suppress injury-induced inflammatory responses, might control the activation and expansion of GR-1(+) macrophages. Interestingly, we found that GR-1(+) macrophage expansion and LPS-induced TNF-alpha expression were not significantly different between wild-type and CD4 T cell-deficient CD4(-/-) mice. However, further investigations showed that LPS-induced TNF-alpha production was significantly influenced by CD4 T cells. Taken together, these data indicate that GR-1(+) F4/80(+) CD11b(+) macrophages represent the primary macrophage subset that expands in response to burn injury and that CD4 T cells do not influence the GR-1(+) macrophage expansion process, but do suppress LPS-induced TNF-alpha production. These data suggest that modulating GR-1(+) macrophage activation as well as CD4 T cell responses after severe injury may help control the development of systemic inflammatory response syndrome and the two-hit response phenotype.