Idiopathic Pulmonary Fibrosis (IPF) is a relentless disease characterized by infiltration of the alveolus with monocytic inflammation and abnormal deposits of collagen. Despite many years of research it remains a terminal diagnosis that affects millions of people worldwide. IPF is associated with TGF-?1 overproduction and the appearance of alternatively activated (M2) macrophages. We have recently shown that inhibition of M2 macrophage differentiation is ameliorative in models of pulmonary fibrosis caused by either bleomycin inhalation or inducible lung targeted TGF-?1 overexpression. Thus, M2 activation is a legitimate target for intervention in pulmonary fibrosis. Little is known about the mechanism(s) through which TGF-?1 induces M2 appearance and accumulation in fibrotic lung disease. We have recently found that TGF-?1 affects M2 phenotypes through a Semaphorin 7a dependent pathway that involves the ?1-integrin subunit. Semaphorin 7a is a GPI anchored membrane protein that we have recently linked to human lung fibrosis. It mediates immunologic events, axon guidance, and tumor invasion through its two known receptors, the ?1-integrin subunit, which associates through the neuronal guidance protein Netrin-1, and Plexin C1. Preliminary work performed in a murine model of TGF-?1 induced lung fibrosis indicates that Semaphorin 7a expression on bone marrow derived cells is sufficient to induce M2 activation and fibrosis and that these effects are mediated via the ?1-integrin subunit. Interestingly, the restoration of fibrosis in this model is associated with impressive induction of Netrin-1 expression. In a simultaneous set of human studies we have found that surface expression of Sema 7a on CD4+ lymphocytes, and mRNA expression of ?1 integrin and Netrin-1 in CD14+ monocytes, is enhanced in the circulation of subjects with IPF. Plexin C1 is not increased. In addition, stimulation of normal CD14+ monocytes with recombinant Sema 7a induces an alternatively activated phenotype and ?1 integrin blockade reduces the CD14+ monocyte to M2 macrophage transition in IPF. The role of Netrin-1 in these processes is not known. This unique constellation of findings leads us to hypothesize that it is the interaction of Semaphorin 7a on CD4+ lymphocytes with the ?1-integrin and Netrin-1 on monocytes that leads to alternative macrophage activation and pulmonary fibrosis.
Aim 1 of this proposal will define the critical cells and mechanisms through which Semaphorin 7a on bone marrow derived cells promotes fibrosis in the TGF-?1-exposed murine lung.
Aim 2 will explore a requirement for Netrin-1 in this process.
Aim 3 will determine the role of the Sema 7a-?1 integrin/Netrin-1 axis in the alternative activation of circulating monocytes obtained from patients with IPF.
Aim 4 will assess the ability of CD4+Sema7a+ cells to function as a biomarker in a cohort of patients with IPF.
This project will use mouse models and primary cells obtained from humans with Idiopathic Pulmonary Fibrosis to determine the novel immunologic mechanisms through which Semaphorin 7a promotes lung fibrosis.
|Sun, Huanxing; Calle, Elizabeth; Chen, Xiaosong et al. (2014) Fibroblast engraftment in the decellularized mouse lung occurs via a *1-integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT. Am J Physiol Lung Cell Mol Physiol 306:L463-75|
|Gan, Ye; Herzog, Erica L (2014) MMP28 and macrophage polarization: orchestrating the attack of the mac. J Leukoc Biol 95:1-3|
|Blackwell, Timothy S; Tager, Andrew M; Borok, Zea et al. (2014) Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189:214-22|
|Murray, Lynne A; Zhang, Huilan; Oak, Sameer R et al. (2014) Targeting interleukin-13 with tralokinumab attenuates lung fibrosis and epithelial damage in a humanized SCID idiopathic pulmonary fibrosis model. Am J Respir Cell Mol Biol 50:985-94|
|Saketkoo, Lesley Ann; Mittoo, Shikha; Frankel, Sid et al. (2014) Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases. J Rheumatol 41:792-8|
|Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte et al. (2014) Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials. Thorax 69:428-36|