The YIN and YANG of lipoproteins in developing and preventing infectious arthritis by Staphylococcus aureus

Abstract

Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus ( S . aureus ). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S . aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S . aureus mutant lacking Lpp diacylglyceryl transferase ( lgt ) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S . aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S . aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.

The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis

“…In contrast to neutrophils, monocytes/macrophages play a vital role in the pathogenesis of S. aureus septic arthritis by aggravating the severity of arthritis in mice 32 . Indeed, the progression of septic arthritis was strongly mediated by monocytes/macrophages through TLR2, but not by neutrophils, in staphylococcal Lpp-induced knee joint arthritis 6 . Chemokines, such as neutrophil chemoattractants KC and MIP-2, are crucial recruiters of neutrophils 33 .…”

“…Chemokines, such as neutrophil chemoattractants KC and MIP-2, are crucial recruiters of neutrophils 33 . Previous studies demonstrated the rapid release of KC in murine peritoneal macrophages upon stimulation by purified staphylococcal Lpp through TLR2 6 . This is in line with our current hematogenous staphylococcal septic arthritis study; Lpp triggered the systemic release of KC to a significantly higher extent than those of the lgt-deficient mutant strain, possibly mediated via TLR2.…”

“…Previously, we showed that staphylococcal Lpp are one of the major arthritogenic bacterial components causing destructive arthritis in wild-type mice but not in TLR2 deficient mice in an animal arthritis model of intra-articular injection of bacterial components 6 . In the current study, a more clinically relevant animal model (hematogenous septic arthritis model) was applied.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ bone erosive effect of Lpp is strictly dependent on TLR2 6 , bone destruction tended to be less pronounced in the TLR2 deficient mice compared to wild-type mice despite displaying more clinical septic arthritis. In other inflammatory conditions, articular bone erosion due to excess generation of osteoclast-mediated local bone resorption and inadequate bone formation is mainly induced by increased expression of cytokines and receptor activator of nuclear factor κB ligand (RANKL) 27 .…”

Lipoproteins Contribute to the Anti-inflammatory Capacity of Lactobacillus plantarum WCFS1

“…For example, lgt and lsp deletion derivatives of Streptococcus equi (Hamilton et al, 2006) and Streptococcus suis (De Greeff et al, 2003), did not display attenuation in their natural hosts (pony and pig, respectively). Moreover, although a Listeria monocytogenes lgt mutant fails to activate TLR2 signaling it is significantly less virulent in a mouse infection model (Machata et al, 2008), whereas lgt mutants of Streptococcus agalactiae (Henneke et al, 2008) and Staphylococcus aureus (Bubeck Wardenburg et al, 2006;Mohammad et al, 2019) are hypervirulent in mouse infection models. These results imply a subtle and strain-specific balance between escaping protective immune defense related to loss of TLR2 activation and attenuated virulence by the loss of lipoprotein acylation in lgt mutants.…”