{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T03:36:46Z","timestamp":1787888206222,"version":"build-2784847793"},"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR060782"],"award-info":[{"award-number":["AR060782"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>It is widely recognized that innate macrophage immune reactions to implant debris are central to the inflammatory responses that drive biologic implant failure over the long term. Less common, adaptive lymphocyte immune reactions to implant debris, such as delayed type hypersensitivity (DTH), can also affect implant performance. It is unknown which key patient factors, if any, mediate these adaptive immune responses that potentiate particle\/macrophage mediated osteolysis. The objective of this investigation was to determine to what degree known adaptive immune responses to metal implant debris can affect particle-induced osteolysis (PIO); and if this pathomechanism is dependent on: 1) innate immune danger signaling, i.e., NLRP3 inflammasome activity, 2) sex, and\/or 3) age. We used an established murine calvaria model of PIO using male and female wild-type C57BL\/6 vs. Caspase-1 deficient mice as well as young (12\u201316 weeks old) vs. aged (18\u201324 months old) female and male C57BL\/6 mice. After induction of metal-DTH, and Cobalt-alloy particle (ASTM F-75, 0.4um median diameter) calvaria challenge, bone resorption was assessed using quantitative micro-computed tomography (micro-CT) analysis and immune responses were assessed by measuring paw inflammation, lymphocyte transformation test (LTT) reactivity and adaptive immune cytokines IFN-gamma and IL-17 (ELISA). Younger aged C57BL\/6 female mice exhibited the highest rate and severity of metal sensitivity lymphocyte responses that also translated into higher PIO compared to any other experimental group. The absence of inflammasome\/caspase-1 activity significantly suppressed DTH metal-reactivity and osteolysis in both male and female Caspase-1 deficient mice. These murine model results indicate that young female mice are more predisposed to metal-DTH augmented inflammatory responses to wear debris, which is highly influenced by active NLRP3 inflammasome\/caspase-1 danger signaling. If these results are clinically meaningful for orthopedic patients, then younger female individuals should be appropriately assessed and followed for DTH derived peri-implant complications.<\/jats:p>","DOI":"10.1371\/journal.pone.0251885","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T17:42:45Z","timestamp":1621359765000},"page":"e0251885","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Metal-induced delayed type hypersensitivity responses potentiate particle induced osteolysis in a sex and age dependent manner"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-1793","authenticated-orcid":true,"given":"Lauryn","family":"Samelko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Caicedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyron","family":"McAllister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6421-2836","authenticated-orcid":true,"given":"Nadim James","family":"Hallab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"issue":"4","key":"pone.0251885.ref001","doi-asserted-by":"crossref","first-page":"780","DOI":"10.2106\/00004623-200704000-00012","article-title":"Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030","volume":"89","author":"S Kurtz","year":"2007","journal-title":"J Bone Joint Surg Am"},{"issue":"2","key":"pone.0251885.ref002","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/000164700317413067","article-title":"Long-term registration has improved the quality of hip replacement: a review of the Swedish THR Register comparing 160,000 cases","volume":"71","author":"P Herberts","year":"2000","journal-title":"Acta Orthop Scand"},{"issue":"5","key":"pone.0251885.ref003","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/000164701753532853","article-title":"The Swedish Knee Arthroplasty Register 1975\u20131997: an update with special emphasis on 41,223 knees operated on in 1988\u20131997","volume":"72","author":"O Robertsson","year":"2001","journal-title":"Acta Orthop Scand"},{"issue":"12","key":"pone.0251885.ref004","doi-asserted-by":"crossref","DOI":"10.3390\/jcm8122091","article-title":"Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment","volume":"8","author":"SB Goodman","year":"2019","journal-title":"J Clin Med"},{"issue":"1","key":"pone.0251885.ref005","first-page":"1","article-title":"Current research in the pathogenesis of aseptic implant loosening associated with particulate wear debris","volume":"79","author":"Y Jiang","year":"2013","journal-title":"Acta Orthop Belg"},{"issue":"Suppl 2","key":"pone.0251885.ref006","first-page":"99","article-title":"Wear 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Res"},{"issue":"7","key":"pone.0251885.ref010","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1136\/ard.56.7.414","article-title":"Human arthroplasty derived macrophages differentiate into osteoclastic bone resorbing cells","volume":"56","author":"A Sabokbar","year":"1997","journal-title":"Ann Rheum Dis"},{"issue":"340","key":"pone.0251885.ref011","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1097\/00003086-199707000-00016","article-title":"Wear particulate species and bone loss in failed total joint arthroplasties","author":"Y Kadoya","year":"1997","journal-title":"Clin Orthop Relat Res"},{"key":"pone.0251885.ref012","first-page":"263625","article-title":"Cytokine-mediated bone destruction in rheumatoid arthritis","volume":"2014","author":"SM Jung","year":"2014","journal-title":"J Immunol Res"},{"issue":"6","key":"pone.0251885.ref013","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/emmm.201201771","article-title":"Of inflammasomes and pathogens\u2014sensing of microbes by the inflammasome","volume":"5","author":"F Bauernfeind","year":"2013","journal-title":"EMBO Mol Med"},{"issue":"6996","key":"pone.0251885.ref014","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nature02664","article-title":"Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf","volume":"430","author":"S Mariathasan","year":"2004","journal-title":"Nature"},{"issue":"1","key":"pone.0251885.ref015","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nri1997","article-title":"Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation","volume":"7","author":"S Mariathasan","year":"2007","journal-title":"Nat Rev Immunol"},{"issue":"7381","key":"pone.0251885.ref016","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nature10759","article-title":"Inflammasomes in health and disease","volume":"481","author":"T Strowig","year":"2012","journal-title":"Nature"},{"issue":"8","key":"pone.0251885.ref017","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/ni.1631","article-title":"Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization","volume":"9","author":"V Hornung","year":"2008","journal-title":"Nat Immunol"},{"issue":"8","key":"pone.0251885.ref018","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/ni.1636","article-title":"The NALP3 inflammasome is involved in the innate immune response to amyloid-beta","volume":"9","author":"A Halle","year":"2008","journal-title":"Nat Immunol"},{"issue":"7293","key":"pone.0251885.ref019","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/nature08938","article-title":"NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals","volume":"464","author":"P 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signaling pathway in human macrophages: a novel mechanism for implant debris reactivity","volume":"27","author":"MS Caicedo","year":"2009","journal-title":"J Orthop Res"},{"issue":"10","key":"pone.0251885.ref023","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1002\/jor.22411","article-title":"Increasing both CoCrMo-alloy particle size and surface irregularity induces increased macrophage inflammasome activation in vitro potentially through lysosomal destabilization mechanisms","volume":"31","author":"MS Caicedo","year":"2013","journal-title":"J Orthop Res"},{"issue":"1","key":"pone.0251885.ref024","doi-asserted-by":"crossref","first-page":"e0210336","DOI":"10.1371\/journal.pone.0210336","article-title":"Transition from metal-DTH resistance to susceptibility is facilitated by NLRP3 inflammasome signaling induced Th17 reactivity: Implications for orthopedic implants","volume":"14","author":"L Samelko","year":"2019","journal-title":"PLoS One"},{"issue":"7","key":"pone.0251885.ref025","doi-asserted-by":"crossref","first-page":"e0160141","DOI":"10.1371\/journal.pone.0160141","article-title":"Cobalt Alloy Implant Debris Induces Inflammation and Bone Loss Primarily through Danger Signaling, Not TLR4 Activation: Implications for DAMP-ening Implant Related Inflammation","volume":"11","author":"L Samelko","year":"2016","journal-title":"PLoS One"},{"issue":"9","key":"pone.0251885.ref026","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1007\/s11999-010-1372-y","article-title":"Histological features of pseudotumor-like tissues from metal-on-metal hips","volume":"468","author":"P Campbell","year":"2010","journal-title":"Clin Orthop Relat Res"},{"issue":"1","key":"pone.0251885.ref027","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.arth.2012.04.010","article-title":"Aseptic lymphocyte dominated vasculitis-associated lesion resulting from trunnion corrosion in a cobalt-chrome unipolar hemiarthroplasty","volume":"28","author":"MM Khair","year":"2013","journal-title":"J Arthroplasty"},{"issue":"1","key":"pone.0251885.ref028","doi-asserted-by":"crossref","first-page":"28","DOI":"10.2106\/00004623-200501000-00006","article-title":"Metal-on-metal bearings and hypersensitivity in patients with artificial hip joints. 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A two-year prospective study","volume":"117","author":"R Kubba","year":"1981","journal-title":"Archives of Dermatology"},{"key":"pone.0251885.ref035","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/0002-9610(80)90323-2","article-title":"Metal allergy and the surgical patient","volume":"139","author":"MB Mayor","year":"1980","journal-title":"The American Journal of Surgery"},{"key":"pone.0251885.ref036","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1365-4362.1981.tb00408.x","article-title":"Metal sensitivity reactions to orthopedic implants","volume":"20","author":"K Merritt","year":"1981","journal-title":"International Journal of Dermatology"},{"key":"pone.0251885.ref037","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0142-9612(84)90066-8","article-title":"Role of medical materials, both in implant and surface applications, in immune response and in resistance to infection","volume":"5","author":"K. Merritt","year":"1984","journal-title":"Biomaterials"},{"issue":"5","key":"pone.0251885.ref038","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3109\/10520297909110677","article-title":"A method for the differentiation of T and B lymphocytes and monocytes migrating under agarose","volume":"54","author":"JA Pinkston","year":"1979","journal-title":"Stain Technology"},{"issue":"4","key":"pone.0251885.ref039","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1302\/0301-620X.62B4.7430234","article-title":"Metal sensitivity in patients undergoing hip replacement. A prospective study","volume":"62-B","author":"GD Rooker","year":"1980","journal-title":"The Journal of Bone and Joint Surgery"},{"key":"pone.0251885.ref040","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3109\/17453678008990769","article-title":"Metal sensitivity in patients with metal-to-plastic total hip arthroplasties","volume":"51","author":"AS Carlsson","year":"1980","journal-title":"Acta Orthop Scand"},{"key":"pone.0251885.ref041","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3109\/17453677708988763","article-title":"Metal sensitivity in patients treated for tibial fractures with plates of stainless steel","volume":"48","author":"M Cramers","year":"1977","journal-title":"Acta Orthopedica Scandinavia"},{"key":"pone.0251885.ref042","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2340\/0001555564121124","article-title":"HLA -A, -B, -C and -DR antigens in individuals with sensitivity to cobalt","volume":"64","author":"T Fischer","year":"1984","journal-title":"Acta Derm Venereol (Stockh)"},{"key":"pone.0251885.ref043","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1600-0536.1976.tb02986.x","article-title":"Rejection of metal to metal prosthesis and skin sensitivity to cobalt","volume":"2","author":"D Munro-Ashman","year":"1976","journal-title":"Contact Dermatitis"},{"key":"pone.0251885.ref044","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1136\/bmj.4.5993.376","article-title":"Incidence of metal sensitivity in patients with total joint replacements","volume":"4","author":"MW Elves","year":"1975","journal-title":"British Medical Journal"},{"key":"pone.0251885.ref045","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1302\/0301-620X.56B4.626","article-title":"Metal sensitivity as a cause of bone necrosis and loosening of the prosthesis in total joint replacement","volume":"56-B","author":"EM Evans","year":"1974","journal-title":"The Journal of Bone and Joint Surgery"},{"issue":"6","key":"pone.0251885.ref046","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1001\/jamainternmed.2013.3271","article-title":"Sex and risk of hip implant failure: assessing total hip arthroplasty outcomes in the United States","volume":"173","author":"MC Inacio","year":"2013","journal-title":"JAMA Intern Med"},{"issue":"8","key":"pone.0251885.ref047","doi-asserted-by":"crossref","first-page":"621","DOI":"10.2106\/JBJS.16.00720","article-title":"Females with Unexplained Joint Pain Following Total Joint Arthroplasty Exhibit a Higher Rate and Severity of Hypersensitivity to Implant Metals Compared with Males: Implications of Sex-Based Bioreactivity Differences","volume":"99","author":"MS Caicedo","year":"2017","journal-title":"J Bone Joint Surg Am"},{"issue":"2","key":"pone.0251885.ref048","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.orthres.2004.09.001","article-title":"Lymphocyte responses in patients with total hip arthroplasty","volume":"23","author":"NJ Hallab","year":"2005","journal-title":"J Orthop Res"},{"issue":"6","key":"pone.0251885.ref049","first-page":"1171","article-title":"Loosening and osteolysis associated with metal-on-metal bearings: A local effect of metal hypersensitivity?","volume":"88","author":"JJ Jacobs","year":"2006","journal-title":"J Bone Joint Surg Am"},{"key":"pone.0251885.ref050","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1749-799X-3-6","article-title":"Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty","volume":"3","author":"NJ Hallab","year":"2008","journal-title":"J Orthop Surg"},{"issue":"2","key":"pone.0251885.ref051","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1002\/jbm.a.32368","article-title":"In vitro reactivity to implant metals demonstrates a person-dependent association with both T-cell and B-cell activation","volume":"92","author":"NJ Hallab","year":"2010","journal-title":"J Biomed Mater Res A"},{"key":"pone.0251885.ref052","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/(SICI)1097-4636(199605)31:1<71::AID-JBM9>3.0.CO;2-N","article-title":"Production of monoclonal antibodies to study corrosion of Co-Cr biomaterials","volume":"31","author":"J Yang","year":"1996","journal-title":"J Biomed Mater Res"},{"key":"pone.0251885.ref053","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/00003086-199605000-00009","article-title":"Immune response to synthetic materials. Sensitization of patients receiving orthopaedic implants","volume":"326","author":"K Merritt","year":"1996","journal-title":"Clin Orthop Rel Res"},{"issue":"5","key":"pone.0251885.ref054","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/ard.39.5.476","article-title":"Metal sensitivity causing loosened joint prostheses","volume":"39","author":"K Christiansen","year":"1980","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"pone.0251885.ref055","doi-asserted-by":"crossref","first-page":"428","DOI":"10.2106\/00004623-200103000-00017","article-title":"Metal sensitivity in patients with orthopaedic implants","volume":"83-A","author":"N Hallab","year":"2001","journal-title":"J Bone Joint Surg Am"},{"issue":"3","key":"pone.0251885.ref056","doi-asserted-by":"crossref","first-page":"257","DOI":"10.2106\/JBJS.18.00134","article-title":"Lymphocyte Transformation Testing (LTT) in Cases of Pain Following Total Knee Arthroplasty: Little Relationship to Histopathologic Findings and Revision Outcomes","volume":"101","author":"S Yang","year":"2019","journal-title":"J Bone Joint Surg Am"},{"issue":"2","key":"pone.0251885.ref057","first-page":"182","article-title":"Biologic effects of implant debris","volume":"67","author":"NJ Hallab","year":"2009","journal-title":"Bull NYU Hosp Jt Dis"},{"issue":"4","key":"pone.0251885.ref058","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/jbm.a.32627","article-title":"Soluble ions more than particulate cobalt-alloy implant debris induce monocyte costimulatory molecule expression and release of proinflammatory cytokines critical to metal-induced lymphocyte reactivity","volume":"93","author":"MS Caicedo","year":"2010","journal-title":"J Biomed Mater Res A"},{"key":"pone.0251885.ref059","doi-asserted-by":"crossref","first-page":"115","DOI":"10.2174\/1874325001812010115","article-title":"CoCrMo alloy vs. UHMWPE Particulate Implant Debris Induces Sex Dependent Aseptic Osteolysis Responses In Vivo using a Murine Model","volume":"12","author":"S Landgraeber","year":"2018","journal-title":"Open Orthop J"},{"issue":"9","key":"pone.0251885.ref060","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.4049\/jimmunol.1300276","article-title":"A critical role for thymic stromal lymphopoietin in nickel-induced allergy in mice","volume":"192","author":"MN Ashrin","year":"2014","journal-title":"J Immunol"},{"issue":"5","key":"pone.0251885.ref061","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/j.1365-2222.2007.02705.x","article-title":"Lipopolysaccharide promotes and augments metal allergies in mice, dependent on innate immunity and histidine decarboxylase","volume":"37","author":"N Sato","year":"2007","journal-title":"Clin Exp Allergy"},{"key":"pone.0251885.ref062","article-title":"TLR4 (not TLR2) dominate cognate TLR activity associated with CoCrMo implant particles","author":"L Samelko","year":"2016","journal-title":"J Orthop Res"},{"issue":"4","key":"pone.0251885.ref063","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.ajo.2008.06.031","article-title":"Nonparametric vs parametric tests of location in biomedical research","volume":"147","author":"CM Kitchen","year":"2009","journal-title":"Am J Ophthalmol"},{"issue":"8","key":"pone.0251885.ref064","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.arth.2004.09.012","article-title":"Immune responses correlate with serum-metal in metal-on-metal hip arthroplasty","volume":"19","author":"NJ Hallab","year":"2004","journal-title":"J Arthroplasty"},{"issue":"10","key":"pone.0251885.ref065","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1002\/1529-0131(200110)44:10<2413::AID-ART406>3.0.CO;2-E","article-title":"Genetic ablation of interferon-gamma up-regulates interleukin-1beta expression and enables the elicitation of collagen-induced arthritis in a nonsusceptible mouse strain","volume":"44","author":"YB Guedez","year":"2001","journal-title":"Arthritis Rheum"},{"issue":"4","key":"pone.0251885.ref066","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/art.21749","article-title":"Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort)","volume":"54","author":"BW Kirkham","year":"2006","journal-title":"Arthritis Rheum"},{"issue":"2","key":"pone.0251885.ref067","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.semarthrit.2013.04.006","article-title":"Th17 cells and IL-17 a\u2014focus on immunopathogenesis and immunotherapeutics","volume":"43","author":"WB van den Berg","year":"2013","journal-title":"Semin Arthritis Rheum"},{"issue":"2","key":"pone.0251885.ref068","first-page":"205","article-title":"Sex-based differences in autoimmune diseases","volume":"52","author":"E Ortona","year":"2016","journal-title":"Ann Ist Super 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