Objective

To determine whether cultured human peritoneal macrophages have functional scavenger receptor(s) and whether activation of macrophages in endometriosis may involve an increase in scavenger receptor activity.

Design

A controlled clinical study comparing peritoneal fluid (PF) macrophages of women with endometriosis and controls without endometriosis.

Setting

Women undergoing laparoscopic evaluation and treatment in a tertiary medical center.

Patient(s)

Twenty-one women undergoing evaluation for pelvic pain or infertility and 10 women undergoing elective laparoscopic tubal ligation.

Intervention(s)

None.

Main outcome measure(s)

Evidence for functional macrophage scavenger receptor and evidence of ligands for the scavenger receptor in PF.

Result(s)

Peritoneal macrophages of women with endometriosis degrade significantly more endothelial cell-low density lipoprotein (EC-LDL) and copper-oxidized LDL (Cu-LDL) than native LDL. Macrophages of women with endometriosis also incorporate more labeled oleic acid into cholesteryl ester in the presence of oxidized LDL (Ox-LDL) than in the presence of native LDL. Western blot analysis demonstrates the presence of adducts between lipid peroxidation products and proteins in PF of patients with and without endometriosis. The PF of women with endometriosis competes with labeled Ox-LDL for uptake by mouse peritoneal macrophages in a dose-dependent manner.

Conclusion(s)

We demonstrate for the first time that human macrophages have functional scavenger receptor(s) and that activation of macrophages in endometriosis involves an increase in scavenger receptor activity. Two lines of evidence indicate the presence of ligands for the scavenger receptor in PF.

Objective

To evaluate for the presence of oxidatively modified lipid-protein complexes in endometriosis and endometrium of women with endometriosis and controls.

Design

Controlled clinical study.

Setting

Academic tertiary care center.

Patient(s)

Women undergoing surgery for pelvic pain, infertility, endometriosis, or tubal ligation controls.

Intervention(s)

Biopsy of endometrium and endometriosis.

Main outcome measure(s)

Staining with antibodies to oxidatively modified lipid proteins (HNE-7, MDA2), macrophages (HAM-56), and muscle cell actin (HHF-35).

Result(s)

Both endometrium and endometriosis tissues contain stromal cells that immunostain with HAM-56 and show immunostaining (both intracellular and extracellular) with HNE-7 and MDA2. Some endometriotic implants show patchy staining with HHF-35. Endometrium was devoid of staining with HHF-35. Control staining with nonimmune sera in both tissues was also devoid of staining.

Conclusion(s)

These data strongly implicate the occurrence of oxidative stress in endometriosis tissue. These data also suggest that oxidative modification is a normal physiological process in endometrium.

Objective

To define the mechanisms underlying the accumulation of monocytes/macrophages in the islets of Langerhans.

Research design and methods

We tested the hypothesis that macrophage accumulation into the islets is caused by overexpression of the chemokine CCL2. To test this hypothesis, we generated transgenic mice and evaluated the cellular composition of the islets by immunohistochemistry and flow cytometry. We determined serum levels of CCL2 by enzyme-linked immunosorbent assay, determined numbers of circulating monocytes, and tested whether CCL2 could mobilize monocytes from the bone marrow directly. We examined development of diabetes over time and tested whether CCL2 effects could be eliminated by deletion of its receptor, CCR2.

Results

Expression of CCL2 by beta-cells was associated with increased numbers of monocytes in circulation and accumulation of macrophages in the islets of transgenic mice. These changes were promoted by combined actions of CCL2 at the level of the bone marrow and the islets and were not seen in animals in which the CCL2 receptor (CCR2) was inactivated. Mice expressing higher levels of CCL2 in the islets developed diabetes spontaneously. The development of diabetes was correlated with the accumulation of large numbers of monocytes in the islets and did not depend on T- and B-cells. Diabetes could also be induced in normoglycemic mice expressing low levels of CCL2 by increasing the number of circulating myeloid cells.

Conclusions

These results indicate that CCL2 promotes monocyte recruitment by acting both locally and remotely and that expression of CCL2 by insulin-producing cells can lead to insulitis and islet destruction.