Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology.
Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T(H)2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T(H)1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.
Herbert
De'Broski R
DR
University of Cape Town, Health Sciences Faculty, 7925 Cape Town, South Africa.
Hölscher
Christoph
C
Mohrs
Markus
M
Arendse
Berenice
B
Schwegmann
Anita
A
Radwanska
Magda
M
Leeto
Mosiuoa
M
Kirsch
Richard
R
Hall
Pauline
P
Mossmann
Horst
H
Claussen
Björn
B
Förster
Irmgard
I
Brombacher
Frank
F
D000818:Animals; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000469:parasitology / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000172:deficiency / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4