Abstract
Recognition of microbial infection by certain intracellular pattern recognition receptors leads to the formation of a multiprotein complex termed the inflammasome. Inflammasome assembly activates caspase-1 and leads to cleavage and secretion of the pro-inflammatory cytokines interleukin-1 beta (IL-1β) and IL-18, which help control many bacterial pathogens. However, excessive inflammation mediated by inflammasome activation can also contribute to immunopathology. Here, we investigated whether Haemophilus ducreyi, a Gram-negative bacterium that causes the genital ulcer disease chancroid, activates inflammasomes in experimentally infected human skin and in monocyte-derived macrophages (MDM). Although H. ducreyi is predominantly extracellular during human infection, several inflammasome-related components were transcriptionally upregulated in H. ducreyi-infected skin. Infection of MDM with live, but not heat-killed, H. ducreyi induced caspase-1-and caspase-5-dependent processing and secretion of IL-1β. Blockage of if. ducreyi uptake by cytochalasin D significantly reduced the amount of secreted IL-1β. Knocking down the expression of the inflammasome components NLRP3 and ASC abolished IL-1β production. Consistent with NLRP3-dependent inflammasome activation, blocking ATP signaling, K+ efflux, cathepsin B activity, and lysosomal acidification all inhibited IL-1β secretion. However, inhibition of the production and function of reactive oxygen species did not decrease IL-1β production. Polarization of macrophages to classically activated M1 or alternatively activated M2 cells abrogated IL-1β secretion elicited by H. ducreyi. Our study data indicate that H. ducreyi induces NLRP3 inflammasome activation via multiple mechanisms and suggest that the heterogeneity of macrophages within human lesions may modulate inflammasome activation during human infection.
| Original language | English |
|---|---|
| Pages (from-to) | 2997-3008 |
| Number of pages | 12 |
| Journal | Infection and Immunity |
| Volume | 81 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2013 |
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ASJC Scopus subject areas
- Immunology
- Microbiology
- Parasitology
- Infectious Diseases
Cite this
Haemophilus ducreyi infection induces activation of the nlrp3 inflammasome in nonpolarized but not in polarized human macrophages. / Li, Wei; Katz, Barry; Bauer, Margaret; Spinola, Stanley.
In: Infection and Immunity, Vol. 81, No. 8, 08.2013, p. 2997-3008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Haemophilus ducreyi infection induces activation of the nlrp3 inflammasome in nonpolarized but not in polarized human macrophages
AU - Li, Wei
AU - Katz, Barry
AU - Bauer, Margaret
AU - Spinola, Stanley
PY - 2013/8
Y1 - 2013/8
N2 - Recognition of microbial infection by certain intracellular pattern recognition receptors leads to the formation of a multiprotein complex termed the inflammasome. Inflammasome assembly activates caspase-1 and leads to cleavage and secretion of the pro-inflammatory cytokines interleukin-1 beta (IL-1β) and IL-18, which help control many bacterial pathogens. However, excessive inflammation mediated by inflammasome activation can also contribute to immunopathology. Here, we investigated whether Haemophilus ducreyi, a Gram-negative bacterium that causes the genital ulcer disease chancroid, activates inflammasomes in experimentally infected human skin and in monocyte-derived macrophages (MDM). Although H. ducreyi is predominantly extracellular during human infection, several inflammasome-related components were transcriptionally upregulated in H. ducreyi-infected skin. Infection of MDM with live, but not heat-killed, H. ducreyi induced caspase-1-and caspase-5-dependent processing and secretion of IL-1β. Blockage of if. ducreyi uptake by cytochalasin D significantly reduced the amount of secreted IL-1β. Knocking down the expression of the inflammasome components NLRP3 and ASC abolished IL-1β production. Consistent with NLRP3-dependent inflammasome activation, blocking ATP signaling, K+ efflux, cathepsin B activity, and lysosomal acidification all inhibited IL-1β secretion. However, inhibition of the production and function of reactive oxygen species did not decrease IL-1β production. Polarization of macrophages to classically activated M1 or alternatively activated M2 cells abrogated IL-1β secretion elicited by H. ducreyi. Our study data indicate that H. ducreyi induces NLRP3 inflammasome activation via multiple mechanisms and suggest that the heterogeneity of macrophages within human lesions may modulate inflammasome activation during human infection.
AB - Recognition of microbial infection by certain intracellular pattern recognition receptors leads to the formation of a multiprotein complex termed the inflammasome. Inflammasome assembly activates caspase-1 and leads to cleavage and secretion of the pro-inflammatory cytokines interleukin-1 beta (IL-1β) and IL-18, which help control many bacterial pathogens. However, excessive inflammation mediated by inflammasome activation can also contribute to immunopathology. Here, we investigated whether Haemophilus ducreyi, a Gram-negative bacterium that causes the genital ulcer disease chancroid, activates inflammasomes in experimentally infected human skin and in monocyte-derived macrophages (MDM). Although H. ducreyi is predominantly extracellular during human infection, several inflammasome-related components were transcriptionally upregulated in H. ducreyi-infected skin. Infection of MDM with live, but not heat-killed, H. ducreyi induced caspase-1-and caspase-5-dependent processing and secretion of IL-1β. Blockage of if. ducreyi uptake by cytochalasin D significantly reduced the amount of secreted IL-1β. Knocking down the expression of the inflammasome components NLRP3 and ASC abolished IL-1β production. Consistent with NLRP3-dependent inflammasome activation, blocking ATP signaling, K+ efflux, cathepsin B activity, and lysosomal acidification all inhibited IL-1β secretion. However, inhibition of the production and function of reactive oxygen species did not decrease IL-1β production. Polarization of macrophages to classically activated M1 or alternatively activated M2 cells abrogated IL-1β secretion elicited by H. ducreyi. Our study data indicate that H. ducreyi induces NLRP3 inflammasome activation via multiple mechanisms and suggest that the heterogeneity of macrophages within human lesions may modulate inflammasome activation during human infection.
UR - http://www.scopus.com/inward/record.url?scp=84880657753&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880657753&partnerID=8YFLogxK
U2 - 10.1128/IAI.00354-13
DO - 10.1128/IAI.00354-13
M3 - Article
C2 - 23753629
AN - SCOPUS:84880657753
VL - 81
SP - 2997
EP - 3008
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 8
ER -