In vitro-derived alternatively activated macrophages reduce colonic inflammation in mice.
OBJECTIVE
Infection with the rat tapeworm Hymenolepis diminuta reduces the severity of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. Infection with H. diminuta increases colonic expression of arginase-1 and found in inflammatory zone 1 (FIZZ1), markers of alternatively activated macrophages (AAMs). We investigated whether AAMs have anticolitic effects.


METHODS
Normal or macrophage-depleted Balb/c mice were infected with H. diminuta; some mice were given DNBS, and the severity of colitis was assessed by disease activity scores, myeloperoxidase activity, and histologic examination. AAMs were also differentiated in vitro, given to mice by intraperitoneal or intravenous injection, and the effects on DNBS-induced colitis were determined. Numbers of AAMs were assessed in biopsy specimens from patients with Crohn's disease.


RESULTS
Depletion of intestinal macrophages using clodronate-liposomes prevented the anticolitic effect of infection with H. diminuta. Injection of AAMs, but not classically activated macrophages, significantly reduced the severity of DNBS-induced colitis. The AAM-induced, anticolitic effect was accompanied by increased interleukin (IL)-10 production from mitogen-stimulated spleen cells; in vivo neutralization of IL-10 partially reduced the effects of AAM transfer. Patients with active CD had reduced numbers of CD68(+)CD206(+) macrophages (which indicate AAM), whereas biopsy specimens from patients with inactive CD had increased numbers of these cells.


CONCLUSIONS
Analysis of the H. diminuta-murine DNBS system identified the AAM, which, when administered to mice, significantly reduced DNBS-induced colitis. The ability to derive AAMs from patients' blood suggests that adoptive transfer of these cells could be a novel approach to inflammatory bowel disease.
Hunter
Meaghan M
MM
Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada.
Wang
Arthur
A
Parhar
Kuljit S
KS
Johnston
Michael J G
MJ
Van Rooijen
Nico
N
Beck
Paul L
PL
McKay
Derek M
DM
D000818:Animals; D001119:Arginase / Q000235:genetics; D001557:Benzenesulfonates; D003092:Colitis / Q000517:prevention & control*; D006801:Humans; D006925:Hymenolepiasis / Q000276:immunology; D048190:Hymenolepis diminuta; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000502:physiology
D001557:Benzenesulfonates; D036341:Intercellular Signaling Peptides and Proteins; C413576:Retnla protein, mouse; C007488:dinitrobenzenesulfonic acid; D016753:Interleukin-10; C544448:Arg1 protein, mouse; D001119:Arginase