Crosstalk between type I and II interferons in regulation of myeloid cell responses during bacterial infection
Introduction
Cells of the immune system communicate by direct cell-cell interactions and by the release and detection of proteinaceous cytokines and other soluble factors. Interferons (IFNs) are a class of cytokines discovered more than 60 years ago and named for their ability to `interfere' with virus infections [1]. Three distinct IFN types (types I, II, and III) are now recognized based on their ability to bind distinct cognate cell surface receptors [2, 3, 4, 5]. The receptor for each IFN type engages signaling pathways involving Janus kinases and signal transducers and activators of transcription (JAK/STAT). However, the details and outcomes of the signaling engaged by each of the receptors differs. This leads to differential effects on inflammatory and immune responses. Variation in expression of the various IFN receptors also shapes how the IFNs impact immune responses. The receptor for type III IFNs (IFNLR) is selectively expressed on epithelial cells, hepatocytes, and a subset of immune cell types while receptors for type I and II IFNs (respectively IFNAR and IFNGR) are constitutively expressed by nearly all nucleated cells [2, 3, 4, 5]. Variation in the magnitude of IFN receptor expression occurs in different cell types and in response to stimulation. Specifically, expression of the IFNGR changes in myeloid cells exposed to IFNαβ or IFNλ [3,6,7]. These and other mechanisms for crosstalk between the IFNs have the potential to suppress, promote, or tune myeloid cell activation in the context of inflammatory and immune responses. In this review, we summarize differences in type I and II IFNs and their beneficial or harmful effects on the host response to bacterial infections. We further review known mechanisms for crosstalk between these cytokines during bacterial infections and how this influences myeloid cell activity and host resistance, with a focus on the suppressive effects type I IFNs have on myeloid cell accumulation and activation at sites of infection.
Section snippets
Canonical cellular responses to type I and II IFNs
Type I IFNs comprise at least 13 IFNα subtypes, IFNβ, IFNδ, IFNε, IFNκ, IFNτ, and IFNω, the genes for which are clustered on mouse chromosome 4 or human chromosome 9 [8]. Nearly all hematopoietic and non-hematopoietic cell types secrete type I IFN proteins in response to stimuli such as viral and bacterial nucleic acids, cyclic-dinucleotides, or lipopolysaccharide. When secreted IFNs bind the heterodimeric IFNAR, JAK1 and TYK2 tyrosine (Tyr) kinases that are constitutively associated with the
Type I and II IFNs have divergent effects on resistance to many bacterial infections
Despite similarities in the type I and II IFN systems and their common ability to induce a subset of antiviral host genes, these cytokines have opposing effects on resistance to bacterial infection. Defects in the response to IFNγ heightens susceptibility to Mycobacteria, Listeria, and other bacteria [17,18]. Mice whose myeloid cells conditionally lack ifngr1 or express a dominant negative IFNGR rapidly succumb to infection by Lm and other intracellular pathogens [19, 20, 21], further
Type I IFNs suppress myeloid cell accumulation at sites of infection
To engulf and kill microbes, myeloid cells must be appropriately recruited to infection foci. IL-1β and TNFα elicit production of pro-inflammatory chemokines and lipid mediators that can promote such recruitment. Both of these mediators are reportedly elevated in fnar1I−/− mice following infection with Lm or Mtb [30, 31, 32], possibly due to reduced expression of Ch25h and thus sterol-response inhibitory 25-hydroxycholesterol [33•]. A recent study further suggested that type I IFN-mediates
IFNγ promotes anti-microbial activation of myeloid cells
Pioneering work by George Mackaness first demonstrated the existence of lymphocyte-derived factors that `activate' macrophages to a state that resists infection by Lm and other pathogenic bacteria [45,46]. Nathan and colleagues subsequently identified IFNγ as the key factor driving this `M1-type' activation [47]. Stimulation of macrophages with IFNγ induces expression of several hundred genes. Many of these GAGs are uniquely or more potently induced by IFNγ versus type I IFNs. Examples include
Type I IFNs inhibit IFNγ-driven activation of myeloid cells
Exposure to microbial products stimulates dendritic cells and some other myeloid cells to release IL-12 and IL-18, which co-stimulate the production of IFNγ by T and innate lymphoid cells. Release of IL-12 and inflammasome activation necessary for IL-18 release can both be inhibited by type I IFNs, potentially reducing IFNγ production during the response to Lm, Mtb, and Staphylococcus aureus [24,30,61]. Though IFNγ still accumulates to stimulatory concentrations in the sera of these infected
Abrogating myeloid cell IFNGR1 reductions improves IFNγ-driven activation and host resistance to bacterial infection
Decreases in myeloid cell surface IFNGR1 staining are preceded by reductions in abundance of ifngr1 transcripts [[70••],64]. The reduced ifngr1 transcripts reflect rapid silencing of de novo transcription at this locus. IFNAR ligation recruits a repressive transcriptional complex to the proximal ifngr1 promoter and promotes histone modifications indicative of transcriptionally inactive chromatin [64]. This transcriptional silencing leads to a rapid reduction in cell surface IFNGR1 protein due
Conclusion
Type I and II IFNs have opposing effects on host resistance to bacterial infection, which correlate with crosstalk between these IFNs. IFNAR ligation suppresses the accumulation of myeloid cells at sites of infection and renders these cells less responsive to IFNγ. Type I IFNs can suppress production of IFNγ by dampening myeloid cell production of IL-12 and act to reduce myeloid cell IFNGR expression. This latter effect renders murine and human myeloid cells less responsive to subsequent
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as
• of special interest
•• of outstanding interest
Acknowledgements
The authors’ work has been funded by research grants from the National Institutes of Health [AI102264, AI103782, AI140499] and the Linda Crnic Institute for Down Syndrome. WJC also received support by a National Institutes of Health Training grant [AI052066]. The sponsors played no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
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