TLR4 (not TLR2) dominate cognate TLR activity associated with CoCrMo implant particles

ABSTRACT Innate immune reactions to orthopedic implant debris are the primary cause of total joint replacement (TJR) failure over the long term (15–20 years). The role of pathogen associated pattern recognition receptors (i.e., TLRs) in regulating immune reactivity to metal implant particles remains controversial. Do different TLRs (i.e., TLR2 vs. TLR4) activated by their respective ligands in concert with metal implant debris elicit equivalent innate immune responses? In this investigation, our in vitro and in vivo data indicate that Gram‐negative PAMPs are more pro‐inflammatory than Gram‐positive PAMPs. In vitro results indicated TLR4 activation in concert with CoCrMo orthopedic implant debris (CoCrMo/LPS+) challenged primary macrophages resulted in significantly greater inflammatory responses than CoCrMo/PAM3CSK+ (TLR2). Similarly, in vivo results indicated CoCrMo/LPS+ TLR4 challenge induced a twofold increase in inflammation‐induced bone resorption (osteolysis) than CoCrMo/PAM3CSK+ (p