Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation  

作　　者：Yugo Morita Motoo Saito Javier Rangel-Moreno Anthony M.Franchini John R.Owen John C.Martinez John L.Daiss Karen L.de Mesy Bentley Stephen L.Kates Edward M.Schwarz Gowrishankar Muthukrishnan 

机构地区：[1]Center for Musculoskeletal Research,University of Rochester Medical Center,Rochester,NY,USA [2]Division of Allergy,Immunology and Rheumatology,Department of Medicine,University of Rochester Medical Center,Rochester,NY,USA [3]Department of Environmental Medicine,University of Rochester School of Medicine and Dentistry,Rochester,NY,USA [4]Department of Orthopedic Surgery,Virginia Commonwealth University,Richmond,VA,USA [5]Department of Orthopedics,University of Rochester Medical Center,Rochester,NY,USA [6]Department of Pathology and Laboratory Medicine,University of Rochester Medical Center,Rochester,NY,USA

出　　处：《Bone Research》2022年第4期826-837,共12页骨研究（英文版）

基　　金：supported by an NIH NIAMS P30 AR069655 pilot grant (G.M.) with additional support from NIH NIAID R21 AI69736 (G.M.);NIH NIAMS P50 AR072000(E.M.S.);P30 AR069655 (E.M.S.);the AO Trauma Clinical Priority Program (E.M.S.,S.L.K.);internal funds of the Department of Medicine and R01A111914 (J.R.M.)。

摘　　要：Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial,and its role in patients with S.aureus osteomyelitis is unknown.To address this knowledge gap,we completed a clinical study and observed elevated serum IL-27 levels(20-fold higher,P<0.05)in patients compared with healthy controls.Remarkably,IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients(P<0.05),suggesting a pathogenic role of IL-27.To test this hypothesis,we evaluated S.aureus osteomyelitis in WT and IL-27Rα^(−/−)mice with and without exogenous IL27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP,respectively.We found that IL-27 was induced at the surgical site within 1 day of S.aureus infection of bone and was expressed by M0,M1 and M2 macrophages and osteoblasts but not by osteoclasts.Unexpectedly,exogenous IL-27p28(~2 ng·mL^(−1) in serum)delivery ameliorated soft tissue abscesses and periimplant bone loss during infection,accompanied by enhanced local IL-27 expression,significant accumulation of RORγt^(+)neutrophils at the infection site,a decrease in RANK^(+) cells,and compromised osteoclast formation.These effects were not observed in IL-27Rα^(−/−)mice compared with WT mice,suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection.In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1,nos2,il17α,il17f,and rorc expression but did not directly stimulate chemotaxis.Collectively,these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S.aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.

关 键 词：ABSCESS protective IMMUNITY 

分 类 号：R681.2[医药卫生—骨科学]