Effects of Small Intestinal Submucosa (SIS) on the Murine Innate Immune Microenvironment Induced by Heat-Killed Staphylococcus aureus

The use of biological scaffold materials for wound healing and tissue remodeling has profoundly impacted regenerative medicine and tissue engineering. The porcine-derived small intestinal submucosa (SIS) is a licensed bioscaffold material regularly used in wound and tissue repair, often in contaminated surgical fields. Complications and failures due to infection of this biomaterial have therefore been a major concern and challenge. SIS can be colonized and infected by wound-associated bacteria, particularly Staphylococcus aureus. In order to address this concern and develop novel intervention strategies, the immune microenvironment orchestrated by the combined action of S. aureus and SIS should be critically evaluated. Since the outcome of tissue remodeling is largely controlled by the local immune microenvironment, we assessed the innate immune profile in terms of cytokine/chemokine microenvironment and inflammasome-responsive genes. BALB/c mice were injected intra-peritoneally with heat-killed S. aureus in the presence or absence of SIS. Analyses of cytokines, chemokines and microarray profiling of inflammasome-related genes were done using peritoneal lavages collected 24 hours after injection. Results showed that unlike SIS, the S. aureus-SIS interactome was characterized by a Th1-biased immune profile with increased expressions of IFN-γ, IL-12 and decreased expressions of IL-4, IL-13, IL-33 and IL-6. Such modulation of the Th1/Th2 axis can greatly facilitate graft rejections. The S. aureus-SIS exposure also augmented the expressions of pro-inflammatory cytokines like IL-1β, Tnf-α, CD30L, Eotaxin and Fractalkine. This heightened inflammatory response caused by S. aureus contamination could enormously affect the biocompatibility of SIS. However, the mRNA expressions of many inflammasome-related genes like Nlrp3, Aim2, Card6 and Pycard were down-regulated by heat-killed S. aureus with or without SIS. In summary, our study explored the innate immune microenvironment induced by the combined exposure of SIS and S. aureus. These results have practical implications in developing strategies to contain infection and promote successful tissue repair.