Chemokines Associated with Pathologic Responses to Orthopedic Implant Debris

Abstract

Despite the success in returning people to health saving mobility and high quality of life, the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after approximately 15-25 years of use, due to slow progressive subtle inflammation to implant debris compromising the bone implant interface. This local inflammatory pseudo disease state is primarily caused by implant debris interaction with innate immune cells, i.e., macrophages. This implant debris can also activate an adaptive immune reaction giving rise to the concept of implant-related metal sensitivity. However, a consensus of studies agree the dominant form of this response is due to innate reactivity by macrophages to implant debris danger signaling (danger-associated molecular pattern) eliciting cytokine-based and chemokine inflammatory responses. This review covers implant debris-induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and how this leads to subsequent implant failure through loosening and osteolysis, i.e., what is known of central chemokines (e.g., IL-8, monocyte chemotactic protein-1, MIP-1, CCL9, CCL10, CCL17, and CCL22) associated with implant debris reactivity as related to the innate immune system activation/cytokine expression, e.g., danger signaling (e.g., IL-1β, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, tumor necrosis factor α, etc.), bone catabolism (e.g., TRAP5b), and hypoxia responses (HIF-1α). More study is needed, however, to fully understand these interactions to effectively counter cytokine- and chemokine-based orthopedic implant-related inflammation.

Keywords: CXC; allergy; chemokines; implant debris; inflammasome; orthopedics.

Figure 1

Schematic of how the innate immune responses particularly inflammasome danger signaling is central to chemokine and cytokine implant debris-induced local inflammation and the pathology of implant loosening/failure (courtesy of Bioengineering Solutions Inc.).

Figure 2

Innate immune system (i.e., macrophage) interactions with implant debris produces danger signaling (inflammasome) and pathogen (NF-κB)-associated cytokines such as IL-1β and tumor necrosis factor α (TNF-α) and increased expression of costimulatory molecules such as CD80/86, ICAM1, and HLADR where the effects on chemokine receptors such as CCR2 and CCR4 are incompletely understood. These innate responses can trigger adaptive immune responses where destructive TH1 type cytokine profiles that then require T-regulatory cells (e.g., IL-10) to control this response (courtesy of BioEngineering Solutions Inc.).

Figure 3

Orthopedic implant debris act on a number of different cells around implants inducing the release of chemokines. Different types of immune cells are recruited by different chemokines. However, there is crossover between the receptors associated with different ligand/chemokines. This schematic highlights the complexity associated with understanding, which key chemokines are best targeted for mitigating implant debris-induced inflammation (–95).