Regulation of Macrophages by Extracellular Matrix Composition and Adhesion Geometry
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The extracellular matrix is a dynamic structural component of tissue and plays a key role in wound healing by providing adhesive cues that regulate cell behavior during tissue repair. Macrophages are essential regulators of inflammation and tissue remodeling, and adaptively change their function in different microenvironments. Although much is known about how soluble factors including cytokines and chemokines influence immune cell function, much less is known about how insoluble cues including those presented by the matrix regulate their behavior. The goal of this study is to understand the potential role of different adhesive proteins and their geometric presentation in regulating macrophage behavior. Previously, using micropatterning and topographical features, we observed that macrophage elongation helps to promote polarization towards a pro-healing phenotype. In this work, we found that adhesion to different extracellular matrix ligands had only a moderate effect on macrophage cytokine secretion in response to prototypical activating stimuli. However, expression of arginase-1, a marker of pro-healing phenotype, was enhanced when cells were cultured on laminin, Matrigel, and vitronectin when compared to collagen, fibronectin, or fibrinogen. When micropatterned into lines, almost all matrix ligands allowed elongation of macrophages and a concomitant increase in arginase-1 expression. Together, these data demonstrate that extracellular matrix composition and adhesion geometry influence macrophage cell shape and function.
In this study, we examined the effects of different extracellular matrix proteins on the phenotypic polarization of macrophages, a major innate immune cell involved in defense against pathogens, wound healing, and progression of many diseases. Our results suggest that the cytokine secretion response of macrophages to inflammatory or wound-healing stimuli was largely independent of the type of adhesion protein on which they were cultured, although laminin, Matrigel, and vitronectin promoted the expression of the pro-healing marker arginase-1. Interestingly, these matrix proteins are all prevalent in tumor environments, where pro-healing macrophages are often observed. Macrophages forced to elongate on patterned substrates of nearly all ECMs increased their expression of arginase-1. The extracellular matrix is dynamic in structure and composition during healing after injury and progression of many diseases including tissue fibrosis, cancer, or cardiovascular disease. This work may provide insight to how adhesion to different matrix environments and geometries regulates macrophages, and their impact on disease.
KeywordsExtracellular matrix Cell elongation Macrophage Polarization
We thank Praveen Krishna Veerasubramanian and Linda McCarthy for technical assistance in the laboratory.
This work was supported by the National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research (NIDCR) Grant DP2DE023319 and National Institute of Allergy and Infectious Diseases (NIAID) Grant 1R21AI128519-01A1.. T. U. L. was supported by a California Institute of Regenerative Medicine (CIRM) Training Fellowship (TG2-01152).
Compliance with Ethical Standards
All protocols involving animals were approved by University of California Irvine’s Institutional Animal Care and Use Committee, which is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALACi).
- 5.Clark RAF, DellaPelle P, Manseau E, Lanigan JM, Dvorak HF, Colvin RB. Blood vessel fibronectin increases in conjunction with endothelial cell proliferation and capillary ingrowth during wound healing. J Investig Dermatol. 1982;79(5):269–76. https://doi.org/10.1111/1523-1747.ep12500076.CrossRefGoogle Scholar
- 19.Du J, Wang Y, Jia L. ECM and atherosclerosis, in Atherosclerosis: risks, mechanisms, and therapies. In: Wang H, Patterson C, editors. Atherosclerosis: risks, mechanisms, and therapies. 1st ed. Hoboken: John Wiley & Sons, Inc; 2015. p. 343–51.Google Scholar
- 21.Wesley RB II, Meng X, Godin D, Galis ZS. Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler Thromb Vasc Biol. 1998;18(3):432–40.CrossRefGoogle Scholar
- 23.Toral D, Zaveri JSL, Dolgova NV, Clare-Salzler MJ, Keselowsky BG. Integrin-directed modulation of macrophage responses to biomaterials. Biomaterials. 2014;35:3504–15. https://doi.org/10.1016/j.biomaterials.2014.01.007. CrossRefGoogle Scholar
- 29.Chen S, Jones JA, Xu Y, Low HY, Anderson JM, Leong KW. Characterization of topographical effects on macrophage behavior in a foreign body response model. Biomaterials. 2010;31(13):3479–91. https://doi.org/10.1016/j.biomaterials.2010.01.074.CrossRefGoogle Scholar
- 43.Swartzlander MD, Lynn AD, Blakney AK, Kyriakides TR, Bryant SJ. Understanding the host response to cell-laden poly(ethylene glycol)-based hydrogels. Biomaterials. 2013;34(4):952–64. https://doi.org/10.1016/j.biomaterials.2012.10.037.CrossRefGoogle Scholar