. Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis.

Background-The systemic response to injury is characterized by massive release of norepinephrine (NE) into the circulation as a result of global sympathetic activation. We have recently demonstrated that NE modulates the recruitment of macrophages to the cutaneous wound. We hypothesized that NE suppresses wound macrophage phagocytic function through canonical adrenergic signaling pathways.

Association between the nervous and immune system is well documented. Immune cells originate within the bone marrow that is innervated. Thermal injury induces adrenergic stimulation, augments monocytopoiesis and alters the β-adrenergic receptor (AR) profile of bone marrow monocyte committed progenitors. This provides an impetus to study AR expression in hematopoietic progenitors along myeloid lineage. Using FACS analysis and confocal microscopy, we report the expression of α1-, α2-and β2-AR in enriched populations of ER-MP20+ and ER-MP12+ myeloid progenitors, CD117+ and CD34+ multi-potential progenitors and more importantly pluripotent stem cells suggesting a plausible role for catecholamine in hematopoietic development.

The mechanism of monocyte deactivation in critically injured burn patients remains unresolved. Two functionally distinct F4/80+Gr-1+ and F4/80+Gr-1- monocyte subsets have been characterized based on their homing to inflammatory or noninflammatory tissues, respectively. We hypothesized that the posttraumatic milieu in the bone marrow (BM) blunts the production of "inflammatory" monocytes. C57Blk/J male mice were divided into sham (S), burn (B), and burn sepsis (BS) groups. B and BS received a 15% dorsal scald burn and BS was inoculated with 15K colony forming units Pseudomonas aeruginosa at the burn site. Animals were killed and blood and femoral BM were collected 48, 72, and 96 hours after injury. ER-MP20 monocyte progenitors were isolated from BM and differentiated into macrophage (MØ) or dendritic cells (DCs) and characterized by the cell surface expression of F4/80 and CD11c, respectively. In both cell types, TLR-4 agonist induced cytokine levels were determined. Results showed a 2-fold increase in the F4/80+Gr-1+ subset at 48 hours in BS that started to decline at 72 hours and remained low at 96 hours. ER-MP20 progenitors isolated at 48 hours exhibited robust MØ differentiation potential but a significant decline in the percentage of the F4/80+Gr-1+ subset (P < .05 vs S) with a concomitant decrease in tumor necrosis factor alpha production. DC development from ER-MP20 progenitors and LPS-stimulated tumor necrosis factor alpha production were impaired. Therefore, BM progenitor derived MØ will replace the transient hyper-responsive circulating monocytes later during the course of the septic insult. Hypo-reactivity of the developing monocytes and DC in the BM and their subsequent egress to the periphery provide a plausible explanation for the immunosuppression that ensues a critical burn injury and sepsis.

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