Bartolacci, Joseph
(2021)
IL-33: An Extracellular Arbiter of Macrophage Mediated Myogenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Volumetric muscle loss (VML) is a debilitating injury associated with chronic disability, and existing treatment options remain unsatisfactory. The current therapeutic gold standard is autologous free-flap grafting; however, the efficacy of this treatment option is limited(Corona, Rivera, Owens, Wenke, & Rathbone, 2015). Biologic scaffolds composed of extracellular matrix (ECM) provide an inductive microenvironment that promotes functional, site appropriate tissue deposition(Dziki, Sicari, Wolf, Cramer, & Badylak, 2016; Dziki, Wang, et al., 2017) and modulation of local immune responses, in particular macrophages. ECM bioscaffolds promote a transition from a pro-inflammatory, M1-like to a pro-healing, M2-like macrophage phenotype that is critical for skeletal muscle tissue healing(Brown, Londono, et al., 2012). However, the component(s) of ECM that govern this phenotypic transition remain poorly understood. Recent studies suggest that matrix-bound nanovesicles (MBV), a component of ECM, may be responsible for ECM-mediated macrophage phenotype activation(L. Huleihel, J. G. Bartolacci, et al., 2017). MBV are an abundant source of extracellular IL-33. IL-33, signaling through the ST2 receptor, is an established mediator of macrophage phenotype(Joshi et al., 2010; H. Xu et al., 2019). Evidence supports non-canonical, ST2-independent IL-33 signaling as a mechanism by which MBV promote a pro-healing macrophage phenotype(G. S. Hussey et al., 2019). However, the nature of MBV-associated IL-33 signaling remains unexplored. The objectives of the present thesis were to determine the phenotypic response of macrophages and muscle stem cells to MBV-associated IL-33, to establish a mechanism for MBV uptake and the resulting localization of delivered MBV cargo, and to interrogate the effects of IL-33 deletion on macrophage phenotype and functional recovery in a mouse model of muscle injury. Results show that ST2-independent IL-33 signaling results in an M2-like macrophage phenotype. MBV-associated IL-33 is internalized by clathrin-mediated endocytosis and is trafficked to the host cell nucleus. IL-33 deletion severely alters the macrophage response to injury and reduces functional recovery in a mouse model of acute skeletal muscle injury. Importantly, delivery of IL-33+ MBV reduced M1-like macrophages and increased force generation. Together, these data show that MBV-associated IL-33 is required for effective repair of skeletal muscle following injury and may represent an extracellular tissue homeostasis signaling molecule.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
26 January 2021 |
| Date Type: |
Publication |
| Defense Date: |
27 April 2020 |
| Approval Date: |
26 January 2021 |
| Submission Date: |
29 July 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
198 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
IL-33, macrophage, VML, ECM |
| Date Deposited: |
26 Jan 2021 14:32 |
| Last Modified: |
26 Jan 2021 14:32 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39480 |
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