RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection

ABSTRACT Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic c...

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Autores principales:	John Satkovich, Christopher J. Anderson, Christopher B. Medina, Matteo Ottolini, John R. Lukens, Melissa M. Kendall
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	RIPK3 Salmonella bacteria macrophages necroptosis systemic infection Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/38648c532ec24fd3aca84aa5122be344
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spelling	oai:doaj.org-article:38648c532ec24fd3aca84aa5122be3442021-11-15T16:19:09ZRIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection10.1128/mBio.02588-202150-7511https://doaj.org/article/38648c532ec24fd3aca84aa5122be3442020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02588-20https://doaj.org/toc/2150-7511ABSTRACT Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic cell death, termed necroptosis. Salmonella enterica serovar Typhimurium is an intracellular pathogen that precisely regulates virulence expression within macrophages to evade and manipulate immune responses, which is a key factor in its ability to cause severe systemic infections. We combined genetic and pharmacological approaches to examine the importance of RIPK3 for S. Typhimurium-induced macrophage death using conditions that recapitulate bacterial gene expression during systemic infection in vivo. Our findings indicate that noninvasive S. Typhimurium does not naturally induce macrophage necroptosis but does so in the presence of pan-caspase inhibition. Moreover, our data suggest that RIPK3 induction (following caspase inhibition) does not impact host survival following S. Typhimurium infection, which differs from previous findings based on inert lipopolysaccharide (LPS) injections. Finally, although necroptosis is typically characterized as highly inflammatory, our data suggest that RIPK3 skews the peritoneal myeloid population away from an inflammatory profile to that of a classically noninflammatory profile. Collectively, these data improve our understanding of S. Typhimurium-macrophage interactions, highlight the possibility that purified bacterial components may not accurately recapitulate the complexity of host-pathogen interactions, and reveal a potential and unexpected role for RIPK3 in resolving inflammation. IMPORTANCE Macrophages employ multiple strategies to limit pathogen infection. For example, macrophages may undergo regulated cell death, including RIPK3-dependent necroptosis, as a means of combatting intracellular bacterial pathogens. However, bacteria have evolved mechanisms to evade or exploit immune responses. Salmonella is an intracellular pathogen that avoids and manipulates immune detection within macrophages. We examined the contribution of RIPK3 to Salmonella-induced macrophage death. Our findings indicate that noninvasive Salmonella does not naturally induce necroptosis, but it does so when caspases are inhibited. Moreover, RIPK3 induction (following caspase inhibition) does not impact host survival following Salmonella systemic infection. Finally, our data show that RIPK3 induction results in recruitment of low-inflammatory myeloid cells, which was unexpected, as necroptosis is typically described as highly inflammatory. Collectively, these data improve our understanding of pathogen-macrophage interactions, including outcomes of regulated cell death during infection in vivo, and reveal a potential new role for RIPK3 in resolving inflammation.John SatkovichChristopher J. AndersonChristopher B. MedinaMatteo OttoliniJohn R. LukensMelissa M. KendallAmerican Society for MicrobiologyarticleRIPK3Salmonellabacteriamacrophagesnecroptosissystemic infectionMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	RIPK3 Salmonella bacteria macrophages necroptosis systemic infection Microbiology QR1-502
spellingShingle	RIPK3 Salmonella bacteria macrophages necroptosis systemic infection Microbiology QR1-502 John Satkovich Christopher J. Anderson Christopher B. Medina Matteo Ottolini John R. Lukens Melissa M. Kendall RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection
description	ABSTRACT Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic cell death, termed necroptosis. Salmonella enterica serovar Typhimurium is an intracellular pathogen that precisely regulates virulence expression within macrophages to evade and manipulate immune responses, which is a key factor in its ability to cause severe systemic infections. We combined genetic and pharmacological approaches to examine the importance of RIPK3 for S. Typhimurium-induced macrophage death using conditions that recapitulate bacterial gene expression during systemic infection in vivo. Our findings indicate that noninvasive S. Typhimurium does not naturally induce macrophage necroptosis but does so in the presence of pan-caspase inhibition. Moreover, our data suggest that RIPK3 induction (following caspase inhibition) does not impact host survival following S. Typhimurium infection, which differs from previous findings based on inert lipopolysaccharide (LPS) injections. Finally, although necroptosis is typically characterized as highly inflammatory, our data suggest that RIPK3 skews the peritoneal myeloid population away from an inflammatory profile to that of a classically noninflammatory profile. Collectively, these data improve our understanding of S. Typhimurium-macrophage interactions, highlight the possibility that purified bacterial components may not accurately recapitulate the complexity of host-pathogen interactions, and reveal a potential and unexpected role for RIPK3 in resolving inflammation. IMPORTANCE Macrophages employ multiple strategies to limit pathogen infection. For example, macrophages may undergo regulated cell death, including RIPK3-dependent necroptosis, as a means of combatting intracellular bacterial pathogens. However, bacteria have evolved mechanisms to evade or exploit immune responses. Salmonella is an intracellular pathogen that avoids and manipulates immune detection within macrophages. We examined the contribution of RIPK3 to Salmonella-induced macrophage death. Our findings indicate that noninvasive Salmonella does not naturally induce necroptosis, but it does so when caspases are inhibited. Moreover, RIPK3 induction (following caspase inhibition) does not impact host survival following Salmonella systemic infection. Finally, our data show that RIPK3 induction results in recruitment of low-inflammatory myeloid cells, which was unexpected, as necroptosis is typically described as highly inflammatory. Collectively, these data improve our understanding of pathogen-macrophage interactions, including outcomes of regulated cell death during infection in vivo, and reveal a potential new role for RIPK3 in resolving inflammation.
format	article
author	John Satkovich Christopher J. Anderson Christopher B. Medina Matteo Ottolini John R. Lukens Melissa M. Kendall
author_facet	John Satkovich Christopher J. Anderson Christopher B. Medina Matteo Ottolini John R. Lukens Melissa M. Kendall
author_sort	John Satkovich
title	RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection
title_short	RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection
title_full	RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection
title_fullStr	RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection
title_full_unstemmed	RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection
title_sort	ripk3-dependent recruitment of low-inflammatory myeloid cells does not protect from systemic <italic toggle="yes">salmonella</italic> infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/38648c532ec24fd3aca84aa5122be344
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RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic <italic toggle="yes">Salmonella</italic> Infection

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