Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection

Abstract

Transendothelial migration of neutrophils in post-capillary venules is a key event in the inflammatory response against pathogens and tissue damage. The precise regulation of this process is incompletely understood. We report that perivascular macrophages are critical for neutrophil migration into skin infected with the pathogen Staphylococcus aureus. Using multiphoton intravital microscopy we show that neutrophils extravasate from inflamed dermal venules in close proximity to perivascular macrophages, which are a major source of neutrophil chemoattractants. The virulence factor alpha-hemolysin lyses perivascular macrophages leading to decreased neutrophil transmigration. Our data illustrate a previously unrecognized role for perivascular macrophages in neutrophil recruitment to inflamed skin, and indicate that Staphylococcus aureus uses hemolysin-dependent killing of these cells as an immune evasion strategy.

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

“…Local macrophages, which provide a rich source of neutrophil chemoattractants KC and MIP-2, are required for neutrophil migration into skin infected with Staphyloccus aureus and subsequent bacterial clearance. 39 However, S. aureus utilizes virulence factor hemolysin to promote rapid macrophage necrosis at the infection site, thereby dampening chemokine generation and neutrophil recruitment. 39 This demonstrates the importance of the initial chemokine wave that is released in response to pathogen infection and highlights responder cell necrosis as a pathogen strategy to terminate it.…”

“…39 However, S. aureus utilizes virulence factor hemolysin to promote rapid macrophage necrosis at the infection site, thereby dampening chemokine generation and neutrophil recruitment. 39 This demonstrates the importance of the initial chemokine wave that is released in response to pathogen infection and highlights responder cell necrosis as a pathogen strategy to terminate it. Indeed, we also found that synthesis of chemokines KC and MIP-2 was rapidly terminated as a consequence of TNF-and LPS-induced necroptosis (Figures 3b and 5d) and translated into impeded neutrophil recruitment to the peritoneal cavity (Figure 6c) and spleen (Figure 7d) in vivo.…”

Leukocyte transendothelial migration: A local affair

“…16 Recently, it has been shown that perivascular macrophages located between the tissue and blood vessels, secrete chemokines that cause local "hotspots" for neutrophil diapedesis in vivo. 17 These chemokines secreted in the extravascular space are bound to glycosaminoglycans (GAGs) and are subsequently transcytosed to the luminal side of the vasculature. There are some indications that oligomeric chemokine-forms activate leukocyte-integrins that direct leukocyte arrest and firm adhesion whereas monomeric-forms activate integrin subsets on the leukocyte that govern cell movement.…”

Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT)

“…ey may be associated with blood vessels (perivascular macrophages) or lymphatic vessels, or may reside in the intervascular spaces [78]. Of note, a recent report has newly de ned the important function of perivascular macrophages in neutrophil recruitment to the skin: neutrophil extravasation occurred in in amed dermal vessels adjacent to perivascular macrophages, and neutrophil in ltration was inhibited when these macrophages were eliminated [79]. Another fundamental role of perivascular macrophages determined through iSALT will be discussed later.…”