The endolysosomal cysteine cathepsins L and K are involved in macrophage‐mediated clearance of Staphylococcus aureus and the concomitant cytokine induction

Abstract

Cysteine cathepsins are endolysosomal cysteine proteases highly expressed in macrophages; however, their individual contributions to the elimination of bacteria and bacteria-induced cytokine production by macrophages are unknown. We assessed the contribution of cysteine cathepsins to macrophage defense pathways against Staphylococcus aureus by using chemical inhibitors and by infecting primary bone marrow-derived macrophages deficient in 1 of 7 major macrophage-expressed endolysosomal cysteine proteases. We show that cysteine cathepsins are involved in the phagocytosis and killing of S. aureus. Cathepsin L was identified as an executor of nonoxidative killing. Moreover, microarray data revealed cysteine cathepsins to be important for the maximal induction of certain proinflammatory genes, such as IL6, in response to S. aureus. Cysteine cathepsin's contribution to IL6 production was dependent on phagocytosis, and cathepsin K was identified to be a critical protease in this process. Analysis of macrophages with impaired trafficking of endolysosomal Toll-like receptors (TLRs) to the acidic compartment revealed that they were not involved in cathepsin-dependent IL6 induction. Because IL6 production was completely dependent on the TLR-adaptor protein myeloid differentiation primary response gene 88 (MyD88), it appears that other TLRs are involved. In summary, lysosomal cysteine proteases are functionally linked to the complex bactericidal and inflammatory activities of macrophages.

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

“…It is not clear whether tick serpins rely on their protease inhibitory activities to regulate the host immune response or not. Muller and colleagues reported that Cathepsins L and K are critical for cytokine production from S. aureus ‐infected macrophages . Our data also suggested that Cathepsins B and G are required for sufficient activation of mouse macrophage by LPS stimulation.…”

“…Cathepsin B was required for optimal posttranslational processing and production of TNF‐α in response to lipopolysaccharide (LPS) . Mice deficient in the serine protease Cathepsin L are much more susceptible to lethal Staphylococcus aureus infection than wild‐type mice . Whether arthropod‐derived serpins regulate host immune responses via their protease inhibitory functions has not been discussed in the previous studies.…”

Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology

“…The assay was performed as previously described (Muller et al, 2014). In brief, macrophages plated in 24 well plates were infected with MRSA (MOI 10) grown in antibiotics overnight.…”

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

“…However, the main focus of research was for a long time on the ubiquitously expressed cathepsins B, D, and L. In contrast, the cysteine cathepsins K and S gained attention only more recently (Arampatzidou et al 2012;Dauth et al 2012;Driessen et al 1999;Friedrichs et al 2003;Muller et al 2014;Pierre and Mellman 1998;Tamhane et al 2014;Tepel et al 2000). This is because of their cell type-specific expression and vital functions, for instance, in the pericellular space (resorption lacuna) of osteoclasts or in the extracellular space Fig.…”