TGF-β-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection.
Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-βRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-β-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-βRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-βRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-β effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.
Infection Immunology, Research Center Borstel, Borstel, Germany.
Lisa
L
Heitmann
Reena
R
Rani
Lucas
L
Dawson
Charles
C
Perkins
Yanfen
Y
Yang
Jordan
J
Downey
Christoph
C
Hölscher
De'Broski R
DR
Herbert
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D004646:Emphysema / Q000209:etiology / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D006725:Hookworm Infections / Q000150:complications / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D007109:Immunity / Q000276:immunology*; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000469:parasitology / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D009559:Nippostrongylus / Q000276:immunology*; D011014:Pneumonia / Q000150:complications / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000150:complications / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014945:Wound Healing
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020782:Matrix Metalloproteinases