Mast cell–macrophage dynamics in modulation of dengue virus infection in skin

Abstract

SummaryDengue virus (DENV) infection causes dengue fever, dengue haemorrhagic fever, or dengue shock syndrome. Mast cells have been speculated to play a role in DENV disease although their precise roles are unclear. In this study, we used mast cell-deficient Kit W-sh/W-sh mice to investigate the involvement of mast cells after intradermal DENV infection. An approximately two-to three-fold higher level of DENV NS3 antigen was detected at the skin inoculation site in DENV-infected Kit W-sh/W-sh mice than in DENV-infected wild-type (WT) mice (using a dose of 1 3 10 9 plaqueforming units/mouse). Moreover, as an indicator of heightened pathogenesis, a more prolonged bleeding time was observed in DENV-infected Kit W-sh/W-sh mice than in WT mice. Monocytes/macrophages are considered to be important targets for DENV infection, so we investigated the susceptibility and chemokine response of DENV-infected peritoneal macrophages from Kit W-sh/W-sh and WT mice both ex vivo and in vivo. There was a tendency for higher DENV infection and higher secretion of CCL2 (MCP-1) from peritoneal macrophages isolated from Kit W-sh/W-sh mice than those from WT mice. In vivo studies using intradermal inoculation of DENV showed about twofold higher levels of infiltrating macrophages and CCL2 (MCP-1) at the inoculation site in both mock control and DENV-inoculated Kit W-sh/W-sh mice than in corresponding WT mice. In summary, compared with WT mice, Kit W-sh/W-sh mice show enhanced DENV infection and macrophage infiltration at the skin inoculation site as well as increased DENV-associated bleeding time. The results indicate an intriguing interplay between mast cells and tissue macrophages to restrict DENV replication in the skin.

Frontline Science: Mast cells regulate neutrophil homeostasis by influencing macrophage clearance activity

“…The synergistic contribution of MC and macrophages in the control of immune responses has been previously studied mainly in the context of inflammation, such as cardiovascular and metabolic diseases and infections . In a recent report, it was shown that MC, through the release of IL‐4, reduce the capacity of peritoneal macrophages to promote bacterial clearance by inhibiting phagocytosis in a sepsis model .…”

“…32 The synergistic contribution of MC and macrophages in the control of immune responses has been previously studied mainly in the context of inflammation, such as cardiovascular and metabolic diseases 33 and infections. 34 In a recent report, it was shown that MC, through the release of IL-4, reduce the capacity of peritoneal macrophages to promote bacterial clearance by inhibiting phagocytosis in a sepsis model. 35 This is apparently in contrast with our findings demonstrating that macrophage phagocytosis of neutrophils is improved in the presence of MC, but conversely suggests that different pathways and/or inflammatory versus homeostatic signals may differentially regulate MC modulation of macrophage functions.…”

Mast cells as protectors of health

“…Studies of DENV infections in MC-deficient mice revealed that recruitment of NK and NKT cells was reduced in the absence of MCs in contrast to an enhanced number of tissue macrophages. 57,69 Therefore localized MC responses to DENV seem to be protective through recruitment of different immune cells and viral clearance. However, on degranulation of infected skin MCs, the virus could be detected within MC granules that were subsequently transported to skin-draining LNs, a process that might contribute to the systemic spread of DENV infection from the initial site of virus invasion.…”

A Role for Human Skin Mast Cells in Dengue Virus Infection and Systemic Spread

“…In addition, mast celldeficient mice have a reduced ability to clear DENV infection, which is thought to be a result of a reduced ability to recruit NKT cells to the infected skin (20). Mast cell-deficient mice also exhibited enhanced DENV infectivity and infiltration of macrophages to the skin inoculation site, and increased DENV-associated bleeding time compared with wild-type mice (22).…”