BMP pathway regulation of and by macrophages.
Pulmonary arterial hypertension (PAH) is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC) treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Megha
M
Talati
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
James
J
West
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Rinat
R
Zaynagetdinov
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Charles C
CC
Hong
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Wei
W
Han
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Tom
T
Blackwell
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Linda
L
Robinson
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Timothy S
TS
Blackwell
Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Kirk
K
Lane
D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism
D051785:Smad Proteins; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II