Foreign Body Responses Adapt to Systemic Immunosuppression to Maintain Local Immune Homeostasis Through Decorin-Associated Signaling

Abstract

Foreign body responses (FBRs) involve complex interactions between pro- and anti-inflammatory signals that regulate the integration and function of implanted biomaterials. However, most mechanistic studies of FBRs have been conducted in healthy hosts, and little is known about how these immune responses are regulated under pathological conditions. Here, we investigated immune responses to porous polycaprolactone (PCL) scaffold implants in mice with endotoxin tolerance or aggressive breast tumors, which induce systemic immunosuppression through distinct mechanisms. Despite suppressed inflammatory activity in major organs, implanted scaffolds maintained locally immune-active environments characterized by increased pro-inflammatory immune-cell populations and elevated inflammatory mediators, including CXCL1. In migration assays, CXCL1 preferentially recruited neutrophils and enriched immune-cell populations with pro-inflammatory phenotypes among splenocytes derived from both endotoxin-tolerant and tumor-bearing mice. The extracellular matrix proteoglycan decorin, a damage-associated molecular pattern with TLR2/4-activating activity in myeloid cells, was enriched within scaffolds but reduced in major organs under both immunosuppressive conditions. Recombinant decorin promoted pro-inflammatory phenotypes in suppressive myeloid-cell populations and enhanced CXCL1 production through TLR2/4-associated signaling, suggesting a mechanistic link between decorin-mediated myeloid activation, CXCL1-dependent immune-cell recruitment, and the maintenance of local immune activity at biomaterial interfaces. Together, these findings reveal that FBRs are not merely passive inflammatory reactions to biomaterial implants but can dynamically adapt to systemic immune dysfunction to sustain local immune homeostasis. This intrinsic immunoregulatory capacity may represent an additional factor influencing the performance of immunomodulatory implants and should be considered in biomaterial design to optimize therapeutic outcomes across different applications and host immune conditions.