Infections of the lung have a greater impact on global health than any other category of disease, and there is an urgent need to better understand antimicrobial defense of the lung. Alveolar macrophages (AMs) are the resident innate immune defenders of the distal lung, and the immunologic repertoire of these cells often differs substantially from that of other phagocytic cells. Among the substances elaborated during infection, lipid mediators derived from arachidonate (eicosanoids), including leukotrienes (LTs) B4 (LTB4) and D4 (LTD4) as well as prostaglandin E2 (PGE2), have emerged as important modulators of innate immune function. Eicosanoids act by ligating specific G protein-coupled receptors on the cell surface and initiating signaling events. We have shown that both LTBB4 (via B LT receptor 1 [BLT1]) and LTD4 (via cysteinyl LT receptor 1 [cysLT1]) promote, while PGE2 (via E prostanoid receptors 2 and 4 [EP2 and EP4]) inhibits, AM capacity for phagocytosis and killing of IgG-opsonized microbes. However, the intracellular mechanisms by which these eicosanoids act are incompletely understood. Although both LT classes promote innate immune functions in AMs, they act via distinct signaling pathways. Likewise, suppression of AM innate immune functions following ligation of EP2 and EP4 is mediated by distinct pathways. As development of pharmacologic agents targeting specific eicosanoid receptors is proceeding rapidly, it is important that the effects of such targeted therapies on antimicrobial defenses of the lung are understood. This project seeks to understand the mechanisms by which these eicosanoids influence key events in the AM signaling pathway triggered by the receptor for opsonic IgG - the Fc3 receptor (FcR). For comparison, events associated with ingestion of the yeast Candida albicans via the mannose receptor (MR) will be studied. The central signaling events we will focus on are activation of: 1) phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN);2) isoforms of protein kinase C (PKC);and 3) small GTPases. The hypothesis is that divergent effects on these phagocytic receptor-triggered signaling components by ligation of BLT1 vs. cysLT1 and EP2 vs. EP4 reflect the differential localization of these receptors to lipid raft membrane microdomains and their differential coupling to two distinct cyclic AMP effectors - protein kinase A (PKA) and exchange protein activated by cyclic AMP (Epac-1). Employing primary rat AMs, we will address specific aims to determine: 1) regulation by PKA and Epac-1 of FcR- and MR-induced signaling events;2) localization to lipid rafts of FcR, MR, and their downstream signaling components and the role of rafts in phagocytosis and killing;3) the roles of PKA vs. Epac-1 and of lipid raft localization in explaining divergent modulation of FcR and MR signaling by BLT1 vs. cysLT1 ligation;4) the roles of PKA vs Epac-1 and of lipid raft localization in explaining divergent modulation of FcR and MR signaling by EP2 vs. EP4 ligation. These proposed studies will provide fundamental insights into AM antimicrobial function, and a clinically relevant framework for understanding and modulating innate immunity in the lung.

Public Health Relevance

Pneumonia has more of an impact on global health than any other category of disease, making it imperative to understand how the lung defends itself from infection. Lipid mediators termed eicosanoids and including leukotrienes and prostaglandins exert potent and opposing effects on the antimicrobial defense functions of the key immune cell in the lung, the alveolar macrophage. The proposed research aims to understand the intracellular events that underlie these eicosanoid effects on alveolar macrophages, thereby providing new clinically relevant insights into regulation of lung defense mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058897-15
Application #
8309216
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
1997-07-10
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2012
Total Cost
$379,150
Indirect Cost
$131,650
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
Zas?ona, Zbigniew; Scruggs, Anne M; Peters-Golden, Marc et al. (2016) Protein kinase A inhibition of macrophage maturation is accompanied by an increase in DNA methylation of the colony-stimulating factor 1 receptor gene. Immunology 149:225-37
Bourdonnay, Emilie; Zas?ona, Zbigniew; Penke, Loka Raghu Kumar et al. (2015) Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling. J Exp Med 212:729-42
Zaslona, Zbigniew; Peters-Golden, Marc (2015) Prostanoids in Asthma and COPD: Actions, Dysregulation, and Therapeutic Opportunities. Chest 148:1300-1306
Degraaf, Angela Juliette; Zas?ona, Zbigniew; Bourdonnay, Emilie et al. (2014) Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation. Am J Respir Cell Mol Biol 51:242-50
Brogliato, Ariane R; Moor, Andrea N; Kesl, Shannon L et al. (2014) Critical role of 5-lipoxygenase and heme oxygenase-1 in wound healing. J Invest Dermatol 134:1436-1445
Monteiro, Ana Paula T; Soledade, Erico; Pinheiro, Carla S et al. (2014) Pivotal role of the 5-lipoxygenase pathway in lung injury after experimental sepsis. Am J Respir Cell Mol Biol 50:87-95
Zas?ona, Zbigniew; Okunishi, Katsuhide; Bourdonnay, Emilie et al. (2014) Prostaglandin E? suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. J Allergy Clin Immunol 133:379-87
Zas?ona, Zbigniew; Przybranowski, Sally; Wilke, Carol et al. (2014) Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma. J Immunol 193:4245-53
O'Brien, E; Bergin, I L; Dolinoy, D C et al. (2014) Perinatal bisphenol A exposure beginning before gestation enhances allergen sensitization, but not pulmonary inflammation, in adult mice. J Dev Orig Health Dis 5:121-31
Wang, Zhuo; Filgueiras, Luciano Ribeiro; Wang, Soujuan et al. (2014) Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation. J Immunol 192:2349-56

Showing the most recent 10 out of 61 publications