Each day, the lungs are exposed to billions of particles whose accumulation can potentially cause infection and damage. While it is crucial to defend against these exposures, it is equally important that protection occurs with minimal physiological disruption or injury caused by inflammation. Mucus and macrophage clearance are hallmark non-inflammatory defenses. Particles and pathogens that deposit in the airways are trapped in mucus and eliminated by ciliary and cough forces, while those in alveoli are ingested by alveolar macrophages (AMs). Using Muc5b knockout mice, we previously showed that Muc5b is required for effective mucociliary clearance and for maintaining healthy pools of resident AMs. The primary objective of this proposal is to determine specific mechanisms by which Muc5b regulates AM function during homeostasis and during acute and resolving inflammation. We have identified a novel mechanism that directly links Muc5b to AM function via sialic acid-binding immunoglobulin-type lectin receptor-F (Siglec-F), an inhibitory immunoreceptor that is expressed selectively by resident AMs and is known to bind ?2,3-linked sialic acid-containing glycoconjugates. Muc5b is ?2,3-sialylated and is an endogenous Siglec-F ligand. We propose that stimulation of Siglec-F by Muc5b calibrates AM inflammatory responses in the resting lung. Thus, in healthy states, the ability of resident AMs to serve protective roles while simultaneously limiting potentially injurious inflammatory responses may occur by a homeostatic programming mechanism mediated by stimulation of Siglec-F by Muc5b. When homeostasis is disrupted by stimuli such as bacteria, a temporary induction of AM inflammatory responsiveness is required. Furthermore, resident AMs are joined by recruited macrophages that arise from circulating monocytes. These recruited monocyte-derived AMs (MDAMs) lack Siglec-F and are highly pro- inflammatory. At the same time that MDAMs are recruited, resident AMs down-regulate their Siglec-F expression and become pro-inflammatory. As inflammation resolves, recruited MDAMs undergo apoptosis and are eliminated, whereas resident AMs restore Siglec-F expression and return to their non-inflammatory states. We postulate that transient reduction of MUC5B:Siglec-F signaling permits an inflammatory response and that restoration of MUC5B:Siglec F signaling is required for its resolution. We hypothesize that stimulation of Siglec-F by Muc5b is a major mechanism for controlling macrophage inflammatory responses during homeostasis and inflammation. We will use wild type and genetically engineered mice, models of acute inflammation, and immunological readouts to test this hypothesis in the following three Specific Aims: 1. Test the hypothesis that during homeostasis, protective AM activities are maintained by MUC5B sialyl glycan- dependent Siglec-F stimulation. 2. Test the hypothesis that MUC5B:Siglec-F dependent inhibitory mechanisms are lost during acute inflammation. 3. Test the hypothesis that re-engagement of MUC5B with Siglec-F on AMs drives the resolution of inflammation.
Our recent discovery that the mucin Muc5b is essential for airway defense showed that Muc5b is crucial for maintaining healthy alveolar macrophages. Furthermore, in models of induced inflammation?including Staphylococcus aureus induced pneumonia?we found that the development of inflammation, and its resolution back to homeostasis, were also tied to Muc5b levels. The studies we propose have the potential to have a highly significant impact on our understanding of the relationship between Muc5b and the alveolar macrophage at the molecular level, and thus could identify novel potential targets for the prevention and treatment of infectious and inflammatory lung diseases.
| Evans, Christopher M; Seibold, Max A; Gerber, Anthony N (2018) SPDEFending the Lung through Mucin Expression. Am J Respir Cell Mol Biol 59:287-288 |
| Evans, Christopher M; Dickey, Burton F; Schwartz, David A (2018) E-Cigarettes: Mucus Measurements Make Marks. Am J Respir Crit Care Med 197:420-422 |
| McCubbrey, Alexandra L; Barthel, Lea; Mohning, Michael P et al. (2018) Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis. Am J Respir Cell Mol Biol 58:66-78 |
| Kumar, Rahul; Mickael, Claudia; Kassa, Biruk et al. (2017) TGF-? activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. Nat Commun 8:15494 |
| Helling, Britney A; Gerber, Anthony N; Kadiyala, Vineela et al. (2017) Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis. Am J Respir Cell Mol Biol 57:91-99 |
| McCubbrey, Alexandra L; Allison, Kristen C; Lee-Sherick, Alisa B et al. (2017) Promoter Specificity and Efficacy in Conditional and Inducible Transgenic Targeting of Lung Macrophages. Front Immunol 8:1618 |
| Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306 |
| Neudecker, Viola; Brodsky, Kelley S; Clambey, Eric T et al. (2017) Neutrophil transfer of miR-223 to lung epithelial cells dampens acute lung injury in mice. Sci Transl Med 9: |
| Livraghi-Butrico, Alessandra; Grubb, Barbara R; Wilkinson, Kristen J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:395-407 |
| Evans, Christopher M; Fingerlin, Tasha E; Schwarz, Marvin I et al. (2016) Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol Rev 96:1567-91 |
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