CXCR2 is critical for bacterial control and development of joint damage and pain in Staphylococcus aureus‐induced septic arthritis in mouse

Abstract

Staphylococcus aureus is the main pathogen associated with septic arthritis. Upon infection, neutrophils are quickly recruited to the joint by different chemoattractants, especially CXCR1/2 binding chemokines. Although their excessive accumulation is associated with intense pain and permanent articular damage, neutrophils have an important function in controlling bacterial burden. This work aimed to study the role of CXCR2 in the control of infection, hypernociception and tissue damage in S. aureus-induced septic arthritis in mice. The kinetics of neutrophil recruitment correlated with the bacterial load recovered from inflamed joint after intra-articular injection of S. aureus. Treatment of mice from the start of infection with the non-competitive antagonist of CXCR1/2, DF2156A, reduced neutrophil accumulation, cytokine production in the tissue, joint hypernociception and articular damage. However, early DF2156A treatment increased the bacterial load locally. CXCR2 was important for neutrophil activation and clearance of bacteria in vitro and in vivo. Start of treatment with DF2156A 3 days after infection prevented increase in bacterial load and reduced the hypernociception in the following days, but did not improve tissue damage. In conclusion, treatment with DF2156A seems be effective in controlling tissue inflammation and dysfunction but its effects are highly dependent on the timing of the treatment start.

LyeTxI-b, a Synthetic Peptide Derived From Lycosa erythrognatha Spider Venom, Shows Potent Antibiotic Activity in Vitro and in Vivo

“…Considering our positive results regarding LyeTxI-b activity in the MIC assay, we evaluated the effectiveness of this peptide in a model of S. aureus -induced arthritis in mice ( Boff et al, 2018 ). Initially, we determined the MIC for S. aureus ATCC 6538, since the strain used in this model was different from the previous MIC assay.…”

Lipoxin A 4 impairs effective bacterial control and potentiates joint inflammation and damage caused by Staphylococcus aureus infection

“…Mouse neutrophils were isolated as previously described. 30 S aureus were incubated at 37°C for 30 minutes in the dark with an equal volume of a 2.0 μM solution of 5(-and 6) carboxyfluorescein diacetate succinimidyl ester (CFDA/SE, Molecular Probes, Eugene, Oregon). After washing three times with PBS to remove excess dye, the bacteria were once again resuspended in PBS to an optical density.…”

“…We have previously shown that the injection of S aureus into the tibiofemoral joint of mice leads to a local inflammatory response that peaks at day 7 after infection. 30 In order to evaluate the role of 5-LO in inflammation and other clinical manifestations in S aureus-induced arthritis, wild type (WT) mice and mice deficient for 5-LO (5-LO −/− ) were infected with S aureus and the inflammatory parameters were evaluated 7 days after the infection. The infection caused massive accumulation of cells into the synovial cavity, mostly neutrophils ( Figure 1A-C), and this was associated with high levels of the chemokines CXCL1 ( Figure 1D) and CCL2 ( Figure 1E) in periarticular tissue.…”

“…In the context of the present study, it has been demonstrated that reactive oxygen species (ROS) produced by macrophages and neutrophils have great importance for S aureus clearance. [29][30][31] Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) is a multicomponent enzyme that mediates electron transfer from nicotinamide adenine dinucleotide phosphate to molecular oxygen. Its isoform NOX2 is expressed in phagocytes, which leads to the production of superoxide anion.…”

Neutrophils: Beneficial and Harmful Cells in Septic Arthritis

“…Neutrophils play a major role in the first-line defense against invading pathogens, including bacteria, and these leukocytes are the first to migrate to the site of infection. Activated macrophages are recruited to the joint slightly later and they are followed by T lymphocytes [ 1 , 14 , 15 , 16 ]. In this manuscript, we will review current knowledge on septic arthritis with an emphasis on the role of neutrophils.…”