TGF-β-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection

Am J Pathol. 2012 Sep;181(3):897-906. doi: 10.1016/j.ajpath.2012.05.032.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Marrow Cells / pathology
  • Emphysema / etiology
  • Emphysema / immunology*
  • Emphysema / parasitology
  • Emphysema / pathology*
  • Hookworm Infections / complications
  • Hookworm Infections / immunology*
  • Hookworm Infections / parasitology
  • Hookworm Infections / pathology
  • Immunity / immunology*
  • Lung / enzymology
  • Lung / immunology
  • Lung / parasitology
  • Lung / pathology
  • Lymphocyte Activation / immunology
  • Macrophages, Alveolar / parasitology
  • Macrophages, Alveolar / pathology
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology*
  • Nippostrongylus / immunology*
  • Pneumonia / complications
  • Pneumonia / immunology
  • Pneumonia / parasitology
  • Pneumonia / pathology
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / metabolism
  • Pulmonary Fibrosis / complications
  • Pulmonary Fibrosis / immunology
  • Pulmonary Fibrosis / parasitology
  • Pulmonary Fibrosis / pathology
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / deficiency
  • Receptors, Transforming Growth Factor beta / metabolism
  • T-Lymphocytes / immunology
  • Transforming Growth Factor beta / metabolism*
  • Wound Healing

Substances

  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Matrix Metalloproteinases