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Serum response factor indirectly regulates type I interferon-signaling in macrophages.

ABSTRACT: Serum response factor (SRF) is required for diverse aspects of development and homeostasis, but potential roles in the regulation of inflammation and immunity have not been systematically investigated. Here, we demonstrate that SRF is unexpectedly required for optimal responses of elicited peritoneal macrophages to type I interferons. Knockdown of SRF expression in these cells impairs induction of numerous interferon (IFN)-stimulated genes (ISGs) in response to zymosan, LPS, and poly I:C. This effect is primarily due to a defect in the ability of induced type I interferons to mediate secondary activation of ISGs. SRF does not appear to be required for expression of established components of the type I interferon signaling pathway, with IFN-?-dependent phosphorylation of STAT1 and STAT2 normally occurring in SRF-depleted macrophages. Collectively, these findings suggest that SRF can indirectly modulate type I interferon-signaling, without interfering with the classic JAK/STAT/ISGF3 pathway.

SUBMITTER: Xie L

PROVIDER: S-EPMC3793656 | biostudies-other | 2013 Oct

REPOSITORIES: biostudies-other

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Serum response factor indirectly regulates type I interferon-signaling in macrophages.

Xie Lan L Sullivan Amy L AL Collier Jana G JG Glass Christopher K CK

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20130525 10

Serum response factor (SRF) is required for diverse aspects of development and homeostasis, but potential roles in the regulation of inflammation and immunity have not been systematically investigated. Here, we demonstrate that SRF is unexpectedly required for optimal responses of elicited peritoneal macrophages to type I interferons. Knockdown of SRF expression in these cells impairs induction of numerous interferon (IFN)-stimulated genes (ISGs) in response to zymosan, LPS, and poly I:C. This e ...[more]

PMID: 23705899

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Project description:Salmonella enterica is an intracellular pathogen that causes diseases ranging from gastroenteritis to typhoid fever. Salmonella bacteria trigger an autophagic response in host cells upon infection but have evolved mechanisms for suppressing this response, thereby enhancing intracellular survival. We recently reported that S. enterica serovar Typhimurium actively recruits the host tyrosine kinase focal adhesion kinase (FAK) to the surface of the Salmonella-containing vacuole (SCV) (K. A. Owen et al., PLoS Pathog 10:e1004159, 2014). FAK then suppresses autophagy through activation of the Akt/mTORC1 signaling pathway. In FAK(-/-) macrophages, bacteria are captured in autophagosomes and intracellular survival is attenuated. Here we show that the cell-autonomous bacterial suppression of autophagy also suppresses the broader innate immune response by inhibiting production of beta interferon (IFN-?). Induction of bacterial autophagy (xenophagy), but not autophagy alone, triggers IFN-? production through a pathway involving the adapter TRIF and endosomal Toll-like receptor 3 (TLR3) and TLR4. Selective FAK knockout in macrophages resulted in rapid bacterial clearance from mucosal tissues after oral infection. Clearance correlated with increased IFN-? production by intestinal macrophages and with IFN-?-dependent induction of IFN-? by intestinal NK cells. Blockade of either IFN-? or IFN-? increased host susceptibility to infection, whereas experimental induction of IFN-? was protective. Thus, bacterial suppression of autophagy not only enhances cell-autonomous survival but also suppresses more-systemic innate immune responses by limiting type I and type II interferons.Salmonella enterica serovar Typhimurium represents one of the most commonly identified bacterial causes of foodborne illness worldwide. S. Typhimurium has developed numerous strategies to evade detection by the host immune system. Autophagy is a cellular process that involves the recognition and degradation of defective proteins and organelles. More recently, autophagy has been described as an important means by which host cells recognize and eliminate invading intracellular pathogens and plays a key role in the production of cytokines. Previously, we determined that Salmonella bacteria are able to suppress their own autophagic capture and elimination by macrophages. Building on that study, we show here that the inhibition of autophagy by Salmonella also prevents the induction of a protective cytokine response mediated by beta interferon (IFN-?) and IFN-?. Together, these findings identify a novel virulence strategy whereby Salmonella bacteria prevent cell autonomous elimination via autophagy and suppress the activation of innate immune responses.

Dataset Information

Serum response factor indirectly regulates type I interferon-signaling in macrophages.

Publications

Serum response factor indirectly regulates type I interferon-signaling in macrophages.

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