Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation

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Abstract
Following trauma, increased inflammatory monokine activation and depressed APC function can occur simultaneously. These contradictory monocyte (Mφ) dysfunctions could result if postinjury Mφ differentiation preferentially favored inflammatory macrophage (Mac) differentiation over development into the most potent APC, dendritic cells (DC). In this report, Mφ of trauma patients with a depressed MLR induction capacity are, for the first time, shown to be unable to differentiate in vitro to immature CD1a+ DC under the influence of GM-CSF and IL-4. Trauma patient Mφ that retained MLR-inducing capacity had a nonsignificant reduction in DC differentiation capacity. Only patient Mφ populations with depressed differentiation to immature DC (iDC) demonstrated depressed IL-12 and IL-15 production and a continued reduced MLR induction capacity. Neither increased IL-10 production nor decreased CD11c+ DC precursor numbers correlated with depressed Mφ-to-DC differentiation. Instead, these patients’ APC-dysfunctional Mφ populations had increased expression of inflammatory Mac phenotypes (CD64+, CD86low, HLA-DRlow) and up-regulated secretion of M-CSF. M-CSF combined with IL-6 inhibits Mφ-to-iDC differentiation and promotes Mφ-to-Mac differentiation by down-regulating GM-CSFR expression and increasing DC apoptosis. Both depressed GM-CSFR expression and increased Mφ iDC apoptosis, as well as increased expression of CD126 (IL-6R) and CD115 (M-CSFR), were detected in APC-defective patient Mφ. In vitro addition of anti-M-CSF enhanced the IL-4 plus GM-CSF-induced Mφ-to-DC differentiation of these patients. This suggests that, in trauma patients, enhanced Mφ-to-Mac differentiation with concomitant inhibited iDC development is partially due to increased circulating Mφ sensitivity to and production of M-CSF and contributes to postinjury immunoaberrations.

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