In order to preserve homeostasis and normal gas exchange function, the lung must restrain inflammatory responses to the continual assault posed by infections, antigens, and toxins. Host responses in the distal lung are dictated in large part by the cross-talk between alveolar epithelial cells (AECs), which comprise the alveolar surface, and alveolar macrophages (AMs), its resident immune cells. Little is known about mechanisms by which AMs control inflammatory responses of AECs. We have recently identified a novel form of intercellular communication in which AMs secrete suppressors of cytokine signaling (SOCS) 1 and 3 proteins within membrane-delimited vesicles that can be taken up by AECs to inhibit inflammatory signaling in response to cytokines in vitro and in vivo. AM secretion of SOCS can be tuned by certain bioactive molecules, including those elaborated by AECs. Furthermore, cigarette smoking reduces while adenoviral infection increases SOCS levels in lung lavage fluid, indicating that dysregulation of SOCS secretion is associated with the known alterations in inflammatory responses that characterize these conditions. This proposal seeks to better understand the fundamental mechanisms, biological consequences, and therapeutic ramifications of this novel form of AM-AEC cross-talk.
Aim 1 will characterize mechanisms regulating the release of two distinct types of vesicles - microparticles and exosomes - and the secretion of SOCS proteins within them, in response to bioactive molecules as well as AEC-derived factors.
Aim 2 will determine the mechanisms controlling uptake of these distinct SOCS-containing vesicles in AECs and the effects of transcellular SOCS delivery on cytokine signaling, inflammatory gene expression, proliferation, and apoptosis in the target cells.
Aim 3 will characterize the operative mechanisms for and consequences of dysregulated SOCS secretion in mouse models of acute inflammation induced by cigarette smoking and adenoviral infection. In addition, the effects and therapeutic potential of synthetic liposomal vesicles loaded with recombinant SOCS proteins will be tested in vitro and in vivo. These studies will provide new insights into the regulation of lung inflammation and a foundation for a novel therapeutic approach to its control.

Public Health Relevance

Cross-talk between macrophages and epithelial cells is essential for the regulation of inflammatory responses in the lung. In this proposal we will examine a previously unrecognized form of cross-talk involving 'injection' of a macrophage anti-inflammatory protein into epithelial cells. The fundamental mechanisms, biological roles, and therapeutic potential of this new mechanism will be investigated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125555-03
Application #
9257198
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Caler, Elisabet V
Project Start
2015-07-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Schneider, Daniel J; Speth, Jennifer M; Penke, Loka R et al. (2017) Mechanisms and modulation of microvesicle uptake in a model of alveolar cell communication. J Biol Chem 292:20897-20910
Speth, Jennifer M; Bourdonnay, Emilie; Penke, Loka Raghu Kumar et al. (2016) Alveolar Epithelial Cell-Derived Prostaglandin E2 Serves as a Request Signal for Macrophage Secretion of Suppressor of Cytokine Signaling 3 during Innate Inflammation. J Immunol 196:5112-20
Schneider, Daniel J; Speth, Jennifer M; Peters-Golden, Marc (2016) Signed, Sealed, Delivered: Microenvironmental Modulation of Extracellular Vesicle-Dependent Immunoregulation in the Lung. Front Cell Dev Biol 4:94
Kovach, Melissa A; Singer, Benjamin H; Newstead, Michael W et al. (2016) IL-36? is secreted in microparticles and exosomes by lung macrophages in response to bacteria and bacterial components. J Leukoc Biol 100:413-21