Interleukin 15 Mediates Joint Destruction in Staphylococcus Aureus Arthritis

Henningsson, Louise; Jirholt, Pernilla; Bogestål, Yalda; Eneljung, Tove; Adiels, Martin; Lindholm, Catharina; McInnes, Iain B.; Bulfone–Paus∥, Silvia; Lerner, Ulf H.; Gjertsson, Inger

doi:10.1093/infdis/jis295

Cited by 15 publications

(14 citation statements)

References 37 publications

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“…The results shown in Fig. S1E and F for groups without antibiotics have been previously published ( 19 ).…”

Section: Resultssupporting

confidence: 66%

“…1E ) during the infection compared to antibiotics with control antibodies. However, the monotherapy of aIL-15ab reduced bacterial clearance and, to a certain extent, also weight loss ( 19 ), but not at all to the same degree as when antibiotics were added (see Fig. S1A to D in the supplemental material).…”

Section: Resultsmentioning

confidence: 98%

“…A delicate balance must be maintained between the immune system's ability to clear the infection and the risk of collateral damage mediated by an overwhelming immune response. We and others have previously shown that inhibition of IL-15 protects against sepsis ( 19 , 22 , 23 ), as well as against both septic and aseptic arthritis development ( 19 – 21 ). We therefore hypothesized that IL-15 might represent a beneficial treatment target to combine with antibiotics in the treatment of S. aureus -induced arthritis.…”

Section: Introductionmentioning

confidence: 92%

“…Serum protein levels of IL-15 increase during experimental S. aureus -induced arthritis and sepsis ( 19 ), and we have previously shown that both IL-15 knockout mice and mice treated with a monotherapy of anti-IL-15 antibodies (aIL-15ab) developed a less destructive S. aureus -induced arthritis than control groups ( 19 ). Furthermore, in other mouse models of aseptic arthritis, as well as in Gram-negative and endotoxin-induced murine sepsis, inhibition of IL-15 has been beneficial with respect to both arthritis development ( 20 , 21 ) and survival during sepsis ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Antibiotics with Interleukin-15 Inhibition Reduce Joint Inflammation and Bone Erosions but Not Cartilage Destruction in Staphylococcus aureus-Induced Arthritis

et al. 2018

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Staphylococcus aureus-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that interleukin-15 (IL-15) inhibition without antibiotics is beneficial in S. aureus-induced arthritis. We therefore hypothesized that the inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would reduce inflammation and joint destruction but preserve the host's ability to clear the infection. Female wild-type C57BL/6 mice were intravenously inoculated with the toxic shock syndrome toxin 1 (TSST-1)-producing LS-1 strain of S. aureus with 0.8 × 108 CFU S. aureus LS-1/mouse. Three days later, treatment consisting of cloxacillin, followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies, was started. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. The addition of aIL-15ab to antibiotics in S. aureus-induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of S. aureus-induced arthritis, such as survival or weight change, or compromise the host's ability to clear the infection. Since the clinical outcome of S. aureus-induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL-15ab and antibiotics is a beneficial, but not optimal, treatment of S. aureus-induced arthritis since it reduces synovitis and bone erosions but has a limited effect on cartilage destruction.

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“…The results shown in Fig. S1E and F for groups without antibiotics have been previously published ( 19 ).…”

Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antibiotics with Interleukin-15 Inhibition Reduce Joint Inflammation and Bone Erosions but Not Cartilage Destruction in Staphylococcus aureus-Induced Arthritis

et al. 2018

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“…Based upon the observation that neutralization of IL-15 by a soluble fragment of IL-15 Ra results in decreased erosions in mice with collagen-induced arthritis (Ruchatz et al, 1998), we recently assessed if IL-15 has any role in joint destruction of mice infected with Staphylococcus aureus. The severity of erosions was robustly decreased in IL-15-deficient mice or by treating wild-type mice with antibodies neutralizing IL-15 (Henningsson et al, 2012). The responses were associated with decreased number of osteoclasts juxtaarticularly.…”

Section: Interleukin-15mentioning

confidence: 97%

The role of cytokines in inflammatory bone loss

Souza

Lerner

2013

Immunological Investigations

224

231

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Chronic inflammatory processes close to bone often lead to loss of bone in diseases such as rheumatoid arthritis, periodontitis, loosened joint prosthesis and tooth implants. This is mainly due to local formation of bone resorbing osteoclasts which degrade bone without any subsequent coupling to new bone formation. Crucial for osteoclastogenesis is stimulation of mononuclear osteoclast progenitors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) which induces their differentiation along the osteoclastic lineage and the fusion to mature, multinucleated osteoclasts. M-CSF and RANKL are produced by osteoblasts/osteocytes and by synovial and periodontal fibroblasts and the expression is regulated by pro- and anti-inflammatory cytokines. These cytokines also regulate osteoclastic differentiation by direct effects on the progenitor cells. In the present overview, we introduce the basic concepts of osteoclast progenitor cell differentiation and summarize the current knowledge on cytokines stimulating and inhibiting osteoclastogenesis by direct and indirect mechanisms.

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Cytokines and Bone: Osteoimmunology

Lorenzo

2020

Handbook of Experimental Pharmacology

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Interleukin 15 Mediates Joint Destruction in Staphylococcus Aureus Arthritis

Abstract: IL-15 is a mediator of joint destruction in S. aureus-induced arthritis and contributes to general morbidity, which makes this cytokine an interesting treatment target in addition to conventional antibiotics.

Cited by 15 publications

References 37 publications

Antibiotics with Interleukin-15 Inhibition Reduce Joint Inflammation and Bone Erosions but Not Cartilage Destruction in Staphylococcus aureus-Induced Arthritis

Antibiotics with Interleukin-15 Inhibition Reduce Joint Inflammation and Bone Erosions but Not Cartilage Destruction in Staphylococcus aureus-Induced Arthritis

The role of cytokines in inflammatory bone loss

Cytokines and Bone: Osteoimmunology

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