The macrophage: orchestrator of the immune response

Phagocytosis is one of the first mechanisms employed by the host to eliminate an invading pathogen. Macrophages (M0) and neutrophils (PMN) are capable of phagocytosis. Neutrophils contain the enzyme myeloperoxidase (MPO) whereas mature M0 are devoid of MPO. It is well-documented that PMNs release MPO into the microenvironment at a site of infection or inflammation where a high percentage of MPO becomes enzymatically inactive (iMPO). Macrophages can acquire MPO via binding of MPO to the M0-mannose receptor. Although the function of MPO in the cytotoxic triad is well documented, the immunoregulatory role of this enzyme has not been elucidated. In this study, in vitro studies were done to determine if either MPO or iMPO could activate M0. The results indicated that M0 exposed to either MPO or iMPO enhanced phagocytosis of Candida albicans as well as M0 candidacidal activity. Another goal of this project was to determine the possible role of MPO or iMPO in rheumatoid arthritis (RA). Resident peritoneal M0 from female Lewis rats were incubated with MPO or iMPO. Subsequently, the supematants were assayed for cytokines associated with RA. These peroxidases activated M0 to secrete pro-inflammatory cytokines. Subsequently, an in vivo rat model was employed. If MPO was injected into an ankle joint of the rat, it did not induce RA. However, if RA was first induced using cell wall fragments derived from group A Streptococci, re-injection of these joints with either MPO or iMPO caused an exacerbation of RA. This exacerbation could be blocked if either anti-tumor necrosis factor alpha or mannan were injected simultaneously with the peroxidase. In addition, the effect of this enzyme on cytokine secretion by endothehal cells, which are present in the joints, was examined. Both forms of the enzyme induced the secretion of pro-inflammatory cytokines. These results taken in their entirety indicate that there is a previously unrecognized interaction between M0 and PMNs in which MPO: (1) activates M0 to be more cytocidal, (2) induces the secretion of pro-inflammatory cytokines, and (3) helps to perpetuate the inflammatory state associated with RA.