Alternatively activated macrophages in intestinal helminth infection: effects on concurrent bacterial colitis.
The distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, including enteric bacterial infections. To dissect the mechanisms by which helminths modulate the host's response to enteric bacteria and bacteria-mediated intestinal inflammation, we have recently established a coinfection model and shown that coinfection with the helminth Heligmosomoides polygyrus exacerbates colitis induced by infection with the gram-negative bacterial pathogen Citrobacter rodentium. The disease severity of the coinfected mice was correlated with high Citrobacter loads in the gut, translocation of the bacteria into mucosal and systemic immune compartments, delayed bacterial clearance, and a significantly enhanced colonic TNF-alpha response. In the present study, using our in vivo coinfection model as well as in vitro approaches, we test the hypothesis that the phenotypic and functional alterations in macrophages induced by the helminth-driven T cell response may contribute to the observed alterations in the response to C. rodentium. We show that via a STAT6-dependent mechanism H. polygyrus coinfection results in a marked infiltration into the colonic lamina propria of F4/80+ cells that have the phenotype of alternatively activated macrophages. Functional analysis of these macrophages further shows that they are impaired in their killing of internalized bacteria. Yet, these cells produce an enhanced amount of TNF-alpha in response to C. rodentium infection. These results demonstrate that helminth infection can impair host protection against concurrent enteric bacterial infection and promote bacteria-induced intestinal injury through a mechanism that involves the induction of alternatively activated macrophages.
Weng
Meiqian
M
Mucosal Immunology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Huntley
Deke
D
Huang
I-Fei
IF
Foye-Jackson
Ondulla
O
Wang
Lijian
L
Sarkissian
Aliese
A
Zhou
Qingping
Q
Walker
W Allan
WA
Cherayil
Bobby J
BJ
Shi
Hai Ning
HN
D000818:Animals; D002465:Cell Movement; D044082:Citrobacter rodentium / Q000276:immunology; D003092:Colitis / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D007411:Intestinal Diseases, Parasitic / Q000150:complications* / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000469:parasitology / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009351:Nematospiroides dubius / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D050800:STAT6 Transcription Factor; D014409:Tumor Necrosis Factor-alpha