Macrophages-Key cells in the response to wear debris from joint replacements

Abstract

The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening, and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of proinflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented.

Keywords: aseptic loosening; inflammation; monocyte/macrophage; osteolysis; tissue homeostasis; total joint replacement; wear particles.

Figure 1

A) Bone resorption by the osteoclast is a two-phase process. Bone is acid demineralized, followed by degradation of the demineralized collagen type I-rich matrix by secreted cathepsin K and other acidic proteinases. B) After one cycle, osteoclasts either undergo apoptosis or initiate a new cycle by moving further. This figure shows toluidine blue stained osteoclast trails (resorption pits) on dentine discs, formed by M-CSF- and RANKL-induced human osteoclasts. M-CSF = macrophage-colony stimulating factor. RANKL = receptor activator of nuclear factor kappa- ligand.

Figure 2

Pattern-recognition receptors (PRRs) recognize wear debris around loose implants. Wear particles are generated from articulating and non-articulating surfaces of artificial joints. Particles with/without carrier proteins are recognized, as such or after phagocytosis, by pattern-recognition receptors (PRRs) including C-type lectin receptors (CLRs), Toll-like receptors (TLRs), nucleotide-binding oligomelization domain (NOD)-like receptors (NLRs) and retinoid acid inducible gene (RIG)-I-like receptors (RLRs) which finally leads to the production of pro-inflammatory cytokines [e.g. tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, interferon (IFN)-γ and type I IFN]. In vitro, implant-derived wear debris was reported to induce NALP3 inflammasome [the neutral apoptosis inhibitor protein (NAIP), MHC class II transcription activator (CIITA), heterokaryon incompatibility locus E protein from Podospora anserine (HET-E) and telomerase-associated protein (TP1) (=NACHT), leucine-rich repeat and pyrin-domain-containing protein 3 or NALP 3 inflammasome]. Wear particles activate the NALP3 inflammasome pathway so that the proinflammatory cytokine precursors pro-IL-1-β, and pro-IL-18 are proteolytically activated by caspase-1. NF-κB = nuclear factor kappa B; NFAT = nuclear factor of activated T-cells; MAPKs = mitogen activated protein kinases; AP-1 = activator protein 1; IRF= interferon regulatory factor.

Figure 3

Initiation and amplification of the inflammatory response is associated with secretion of several cytokines and other substances from cells stimulated by pathogen/microbial-associated molecular patterns (PAMP/MAMP) or alarmins such as LPS, bacterial cell wall structures, bacterial DNA, damaged cell components, etc. recognized through pattern-recognizing receptors (PRRs) such as cell surface or intracellular Toll-like receptors (TLRs) and strictly intracellular nucleotide oligomerisation domain-like receptors (NLRs), or cellular damage sensing receptor for advanced glycation endproducts (RAGE) and others. Wear particles, once coated with host-related danger signals or other opsonins particles, could contribute substantially to the above inflammatory stimulation predominantly by increasing the expression of several pro-inflammatory cytokines such as IL-1, TNF-α, and IL-6. Intracellular pathways responsible for inflammatory responses to TLR, IL-1 receptor and TNF-α receptor stimulation use several common crucial factors such as transforming growth factor-activated kinase 1 (TAK1), which is involved in the activation of canonical pro-inflammatory transcription factors NF-κB and c-JUN member of AP-1. Both transcription factors are responsible for transcription initiation of pro-inflammatory cytokines and mediators (IL-1β, IL-6, IL-12, IL-15, IL-8, TNF-α, LT-α, PGE2) but also for the expression of growth factors (GM-CSF) and Th1 stimulators IFN-γ. Two factors are important for modulation of the inflammatory response: homodimeric form of NF-κB (p50/p50) and p38. For example p50/p50 could suppress the expression of TNF-α. The role of p38 can both support inflammation by promoting expression of proinflammatory cytokines and prevent inflammatory responses for example by p38 controlled expression of important anti-inflammatory factors that limit inflammation and contribute to its resolution (IL-10).

Figure 4

Wear particles (WP) or pathogen-associated molecular patterns like lipopolysaccharide (LPS) together with IFN-γ produced by NK cell and several cytokines (IL-3, GM-CSF, TNF-α) induce macrophage polarization toward the classical M1 phenotype, characterized by the production of pro-inflammatory cytokines IL-1β, IL-6, Th1-polarizing cytokine IL-12, Th17 maturation-inducing cytokine IL-23, reactive oxygen species (ROS), and reactive nitrogen species (RNS) promoting and perpetuating thus inflammation. Other factors like IL-4, IL-13, α-tocopherol stimulate macrophage polarization toward alternatively activated - M2 macrophage, characterized by production of IL-10, IL-1 receptor antagonist (IL-1RA), arginase 1, Fizz 1, chitinase-like protein (Ym-1), polyamines, ornithin, factors involved in antiinflammatory response or resolution of inflammation, tissue remodeling and repair, foreign-body type response (encapsulation), anti-parasite defense (Ym-1), and generally suppression of Th1 functions. During macrophage polarization Krüppel-like factor 4 (KLF4) plays a decisive role. KLF4 expression is increased in M2 macrophages and dramatically reduced in M1 macrophages. KLF4 cooperates with STAT6 to induce an M2 polarization and to inhibit an M1 via sequestration of coactivators of NF-κB. Wear particles deliberated from the prosthetic surfaces coated by type I collagen, aggrecan, proteoglycans and immunoglobulins serve as strong facilitators during macrophage polarization.

Figure 5

Simplified overview of the potential targets influencing macrophage-signaling pathways related to periprosthetic osteolysis (OL) and total hip arthroplasty aseptic loosening (THA-AL). In blue - gene polymorphisms (GP) affecting: receptors (a); individual proteins of intracellular signaling pathways (b); non-coding sequences of involved genes (promoter and response elements, enhancers, introns, polyadenylation signal) (c); GP affecting structure and activity of chemokines, cytokines and effector molecules (d). In green - posttranscriptional regulation (e.g. regulatory miRNA, epigenetic regulation of gene-expression) (a); GP affecting processing enzymes and proteins involved in posttranslational modifications, intracellular transport, and processing (b). In yellow - currently described SNP targets supposed to be associated with increased risk of AL (IL-1 receptor; matrix metalloproteinase 1 (MMP-1); IL-6 and TNF-α; SNP in TNF-α promoter associated with reduced binding of inhibitory p50 homodimers). Note that when one or even several of proposed “pro-osteolytic GPs” (even in the key molecules) are found in a patient, it does not automatically mean that large osteolysis develops around his or her TJR. Such abnormalities may be well compensated by other pathways involved in complex signaling network running in periprosthetic tissues.