Cargando…

Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection

Group A Streptococcus (GAS, Streptococcus pyogenes) is a professional human pathogen that commonly infects the skin. Keratinocytes are one of the first cells to contact GAS, and by inducing inflammation, they can initiate the earliest immune responses to pathogen invasion. Here, we characterized the...

Descripción completa

Detalles Bibliográficos
Autores principales: Johnson, Anders F., Sands, Jenna S., Trivedi, Keya M., Russell, Raedeen, LaRock, Doris L., LaRock, Christopher N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138833/
https://www.ncbi.nlm.nih.gov/pubmed/37068092
http://dx.doi.org/10.1371/journal.ppat.1011321
_version_ 1785032800467943424
author Johnson, Anders F.
Sands, Jenna S.
Trivedi, Keya M.
Russell, Raedeen
LaRock, Doris L.
LaRock, Christopher N.
author_facet Johnson, Anders F.
Sands, Jenna S.
Trivedi, Keya M.
Russell, Raedeen
LaRock, Doris L.
LaRock, Christopher N.
author_sort Johnson, Anders F.
collection PubMed
description Group A Streptococcus (GAS, Streptococcus pyogenes) is a professional human pathogen that commonly infects the skin. Keratinocytes are one of the first cells to contact GAS, and by inducing inflammation, they can initiate the earliest immune responses to pathogen invasion. Here, we characterized the proinflammatory cytokine repertoire produced by primary human keratinocytes and surrogate cell lines commonly used in vitro. Infection induces several cytokines and chemokines, but keratinocytes constitutively secrete IL-18 in a form that is inert (pro-IL-18) and lacks proinflammatory activity. Canonically, IL-18 activation and secretion are coupled through a single proteolytic event that is regulated intracellularly by the inflammasome protease caspase-1 in myeloid cells. The pool of extracellular pro-IL-18 generated by keratinocytes is poised to sense extracellular proteases. It is directly processed into a mature active form by SpeB, a secreted GAS protease that is a critical virulent factor during skin infection. This mechanism contributes to the proinflammatory response against GAS, resulting in T cell activation and the secretion of IFN-γ. Under these conditions, isolates of several other major bacterial pathogens and microbiota of the skin were found to not have significant IL-18-maturing ability. These results suggest keratinocyte-secreted IL-18 is a sentinel that sounds an early alarm that is highly sensitive to GAS, yet tolerant to non-invasive members of the microbiota.
format Online
Article
Text
id pubmed-10138833
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-101388332023-04-28 Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection Johnson, Anders F. Sands, Jenna S. Trivedi, Keya M. Russell, Raedeen LaRock, Doris L. LaRock, Christopher N. PLoS Pathog Research Article Group A Streptococcus (GAS, Streptococcus pyogenes) is a professional human pathogen that commonly infects the skin. Keratinocytes are one of the first cells to contact GAS, and by inducing inflammation, they can initiate the earliest immune responses to pathogen invasion. Here, we characterized the proinflammatory cytokine repertoire produced by primary human keratinocytes and surrogate cell lines commonly used in vitro. Infection induces several cytokines and chemokines, but keratinocytes constitutively secrete IL-18 in a form that is inert (pro-IL-18) and lacks proinflammatory activity. Canonically, IL-18 activation and secretion are coupled through a single proteolytic event that is regulated intracellularly by the inflammasome protease caspase-1 in myeloid cells. The pool of extracellular pro-IL-18 generated by keratinocytes is poised to sense extracellular proteases. It is directly processed into a mature active form by SpeB, a secreted GAS protease that is a critical virulent factor during skin infection. This mechanism contributes to the proinflammatory response against GAS, resulting in T cell activation and the secretion of IFN-γ. Under these conditions, isolates of several other major bacterial pathogens and microbiota of the skin were found to not have significant IL-18-maturing ability. These results suggest keratinocyte-secreted IL-18 is a sentinel that sounds an early alarm that is highly sensitive to GAS, yet tolerant to non-invasive members of the microbiota. Public Library of Science 2023-04-17 /pmc/articles/PMC10138833/ /pubmed/37068092 http://dx.doi.org/10.1371/journal.ppat.1011321 Text en © 2023 Johnson et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Johnson, Anders F.
Sands, Jenna S.
Trivedi, Keya M.
Russell, Raedeen
LaRock, Doris L.
LaRock, Christopher N.
Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection
title Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection
title_full Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection
title_fullStr Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection
title_full_unstemmed Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection
title_short Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection
title_sort constitutive secretion of pro-il-18 allows keratinocytes to initiate inflammation during bacterial infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138833/
https://www.ncbi.nlm.nih.gov/pubmed/37068092
http://dx.doi.org/10.1371/journal.ppat.1011321
work_keys_str_mv AT johnsonandersf constitutivesecretionofproil18allowskeratinocytestoinitiateinflammationduringbacterialinfection
AT sandsjennas constitutivesecretionofproil18allowskeratinocytestoinitiateinflammationduringbacterialinfection
AT trivedikeyam constitutivesecretionofproil18allowskeratinocytestoinitiateinflammationduringbacterialinfection
AT russellraedeen constitutivesecretionofproil18allowskeratinocytestoinitiateinflammationduringbacterialinfection
AT larockdorisl constitutivesecretionofproil18allowskeratinocytestoinitiateinflammationduringbacterialinfection
AT larockchristophern constitutivesecretionofproil18allowskeratinocytestoinitiateinflammationduringbacterialinfection