The regulatory landscape of macrophage interferon signaling in inflammation

Abstract

The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunologic adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, such as SLE. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage’s role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment. The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunologic adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, such as SLE. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage’s role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment. Interferons (IFNs) underlie the competence of the innate immune system to ward off pathogens. In viral infections, IFNs are secreted to induce an antiviral state in host cells, supporting our first line of defense against pathogens.1Durbin J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Frey A.B. Moran T.M. et al.Type I IFN modulates innate and specific antiviral immunity.J Immunol. 2000; 164: 4220-4228Crossref PubMed Google Scholar Moreover, IFNs recruit leukocytes to the site of infection and augment their activity.2Lee A.J. Ashkar A.A. The dual nature of type I and type II interferons.Front Immunol. 2018; 9: 2061Crossref PubMed Scopus (343) Google Scholar These measures ultimately aim to interfere with viral replication and dissemination, curtailing the infection. Perturbed IFN responses may therefore underlie severity and susceptibility to viral infections.3Posseme C. Llibre A. Charbit B. Bondet V. Rouilly V. Saint-André V. et al.Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation.Cell Rep. 2022; 39110989Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Predictably, impaired IFN responses are a hallmark of severe COVID-19 manifestation.4Stertz S. Hale B.G. Interferon system deficiencies exacerbating severe pandemic virus infections.Trends Microbiol. 2021; 29: 973-982Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,5Hadjadj J. Yatim N. Barnabei L. Corneau A. Boussier J. Smith N. et al.Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.Science (1979). 2020; 369: 718-724Crossref PubMed Scopus (0) Google Scholar More than half a century of research since their discovery, the role of IFNs is now known to extend well beyond antiviral responses. Namely, IFNs orchestrate various distinct homeostatic processes and immune responses to maintain physiological integrity.6Place D.E. Malireddi R.K.S. Kim J. Vogel P. Yamamoto M. Kanneganti T.D. Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins.Nat Commun. 2021; 12: 1-9Crossref PubMed Scopus (35) Google Scholar,7Katlinskaya Y.V. Katlinski K.V. Lasri A. Li N. Beiting D.P. Durham A.C. et al.Type I interferons control proliferation and function of the intestinal epithelium.Mol Cell Biol. 2016; 36: 1124-1135Crossref PubMed Scopus (26) Google Scholar Accordingly, disconcerted IFN responses have long been implicated to drive various autoinflammatory disorders, such as SLE and Aicardi-Goutières syndrome. In addition, IFNs commonly contribute to local or systemic inflammation as seen in rheumatoid arthritis and macrophage activation syndrome. Because perturbed IFN signaling appears as a common denominator in these conditions, they are now widely recognized as so-called interferonopathies. The pervasive role of IFNs necessitates investigative efforts into all facets of the IFN system to infer clinically relevant targets to reduce the burden of inflammatory disease. The IFN system is directed toward interfering with microbial dissemination, principally by enhancing interferon-stimulated gene (ISG) expression. On infection, nearly any host cell will produce IFNs as an intrinsic response against microbials, but also to protect neighboring cells and activate leukocytes. Purposely, some leukocytes are competent producers of IFNs themselves and highly responsive to the regulatory effects of IFNs, forming a feed-forward loop. The capacity of leukocytes to produce IFNs is dependent on cell lineage and cellular microenvironment, like the presence of pathogens and cytokines. Classically, there are lineages of cells specialized in the secretion of specific types of IFNs. For instance, plasmacytoid dendritic cells are accepted to be the predominant producers of type I and type III IFNs, whereas T cells are the foremost type II IFN-secreting leukocytes.8Fitzgerald-Bocarsly P. Dai J. Singh S. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history.Cytokine Growth Factor Rev. 2008; 19: 3Crossref PubMed Scopus (261) Google Scholar, 9Psarras A. Alase A. Antanaviciute A. Carr I.M. Md Yusof M.Y. Wittmann M. et al.Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize Commun. 2020; PubMed Scopus Google Scholar, Dai J. J. M. et al.Type III IFNs are by and plasmacytoid dendritic Immunol. PubMed Scopus Google Scholar, of innate and immune Immunol. PubMed Scopus Google Scholar various leukocytes have been S. A. L. J. S. of type I interferons in infectious plasmacytoid dendritic cells in the Immunol. PubMed Scopus Google Scholar, L. et of by macrophages at the with PubMed Scopus Google Scholar, C. S. B. et of innate PubMed Scopus Google Scholar, A. M. S. et macrophages are producers of interferons and macrophages are 2020; Full Text Full Text PDF PubMed Scopus Google Scholar the of the IFN The dual nature of and from their role in and C. M. A.C. of macrophages in understanding on Immunol. 2021; 12: Scholar macrophages are of by on the role of and in innate immune responses. recognition a of macrophages to such as The to for IFN responses are such as and such as gene and gene their of and to viral and macrophages to an of in response to their the of an IFN Apart from IFNs, macrophages are responsive to IFNs, in the center of the IFN J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Frey A.B. Moran T.M. et al.Type I IFN modulates innate and specific antiviral immunity.J Immunol. 2000; 164: 4220-4228Crossref PubMed Google S. A. L. J. S. of type I interferons in infectious plasmacytoid dendritic cells in the Immunol. PubMed Scopus Google Scholar this role also macrophages in interferons in 2020; Scopus Google A. Li M. of systemic a cellular Full Text Full Text PDF PubMed Scopus Google Scholar for the of processes the IFN on regulatory This will the understanding of regulatory IFN responses in macrophages. of IFNs is their ability to cellular to immunologic These effects first than 50 years and are to be a function of PubMed Google Scholar the IFN system is established to of type and III IFNs. are of type I and and III IFNs to and a type II IFN The of these is but to and of and Immunol. 2021; Scopus Google M. J. J. of type I interferons Biol. PubMed Scopus Google Scholar the types of IFNs S. M. et of (1979). PubMed Google Scholar, A. P. et of by Full Text Full Text PDF PubMed Google Scholar, M. M. S. The of interferon at A. PubMed Scopus (0) Google Scholar Accordingly, of IFNs a distinct signaling is their regulatory immunomodulating effects or the binding of type I IFNs to and triggers and to and of and IFN regulatory to gene type II IFN and leading to and and of The activation will to the to whereas response the of III IFNs a of and their downstream signaling with type I IFNs are downstream of with antimicrobial to protect the host from of the are with and are also a in the of various are the control of in all of the viral from to they all PubMed Scopus Google Scholar are in viral infections, but IFNs in is is known the of is for to pathogens in a to viral infections, by of replication and L. V. I interferon against disease by the PubMed Scopus Google Scholar, M.Y. Smith M. et interferon gene in Rep. 9: PubMed Scopus Google Scholar, N. A.A. J. S. et of interferon responses by 2022; Full Text Full Text PDF PubMed Scopus (0) Google Scholar, S. S. S. M. J. et is a the of Commun. PubMed Scopus Google Scholar IFNs contribute to by the secretion of and A.J. B. et type I interferon signaling to activate cells a viral PubMed Scopus Google A. an leading to of and type I Immunol. 2008; 9: PubMed Scopus Google Scholar IFNs as of inflammatory responses, the inflammatory response of C. Llibre A. Charbit B. Bondet V. Rouilly V. Saint-André V. et al.Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation.Cell Rep. 2022; 39110989Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar is a inflammatory by the J. A. L. A. N. et al.Type I IFN in an and to for of and in Immunol. PubMed Scopus (0) Google Scholar secretion is by an and type I IFN loop. On cell macrophages will an inflammatory the secretion of IFNs. The type I IFNs the macrophage’s ability to produce B. M. et of in macrophages by and type I interferons.Front Immunol. PubMed Scopus Google M. et and type in PubMed Scopus Google Scholar These findings type I IFNs to a regulatory to macrophages to inflammation and the ability of type II IFN to induce antiviral responses, is a of macrophages by enhancing the of macrophage in their or the of type II IFN is the of through macrophages to recruit the of B. of and in immune 2020; PubMed Scopus Google Scholar type II IFN the of by immunologic of the such as and secretion of inflammatory and M. in infectious 2018; 9: PubMed Scopus Google Scholar The of type II IFN to the macrophage’s phenotype is by ability to to inflammatory in of M. S. et into highly macrophages a phenotype relevant to Immunol. 2021; PubMed Scopus Google Scholar the type I and II IFN are type I and II IFN signaling have been to These effects are by the ability of type I IFNs to also and type II IFN to C. I interferon activation of and signaling Immunol. 2020; Scopus Google Scholar, M. M. C. et of interferon Biol. 2020; PubMed Scopus Google Scholar, A. C. M. et from to gene Commun. PubMed Scopus Google Scholar IFNs to into the of types of IFNs, in the cellular response to types of IFNs. These effects are in macrophages or the of J. et inflammatory responses to type I interferon in or Immunol. 2022; Full Text Full Text PDF PubMed Scopus (0) Google Scholar the is macrophages a gene commonly with type II IFN to type III IFNs, first in they the recent to the IFN V. A. M. et antiviral against virus infection host Full Text Full Text PDF PubMed Scopus Google A. M. et antiviral through a distinct II Immunol. PubMed Scopus Google Scholar efforts are directed toward understanding the of type III IFNs a IFN system type I and type II IFNs. a local and role of type III IFNs, whereas type I IFNs induce a systemic immune V. A. M. et antiviral against virus infection host Full Text Full Text PDF PubMed Scopus Google M. 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PubMed Scopus Google Scholar, The intestinal immune responses and Immunol. 9: PubMed Scopus Google Scholar in such as the and bone in IFN signaling in the of A. and type I IFN responses in inflammatory Rep. 2018; Full Text Full Text PDF PubMed Scopus (26) Google Scholar IFN signaling in and this to be to their antiviral in immunologic responses, cells The IFN is to and IFNs as to the of in D.E. Malireddi R.K.S. Kim J. Vogel P. Yamamoto M. Kanneganti T.D. Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins.Nat Commun. 2021; 12: 1-9Crossref PubMed Scopus (35) Google Scholar This homeostatic role of IFN is by type I or type II IFNs, they bone N. M. Li et a role in bone in and in PubMed Scopus (0) Google S. C. Li A. L. et novel role for interferon regulatory in of bone Cell PubMed Scopus Google Scholar bone is with inflammatory such as SLE and rheumatoid disease in 2018; PubMed Scopus (26) Google N. C. 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C. et an antiviral innate immune function the Scopus Google Scholar These findings support an underappreciated regulatory role of in immunity. activation of macrophages local and systemic through the presence of cells distinct the inflammatory of macrophages the presence of regulatory to their inflammatory to commonly with an inflammatory macrophage In the of macrophages is they to be in response to their In with their ability to regulate the of in response to a of and distinct N. S. of with immune activation of macrophages and type I interferon PubMed Scopus (0) Google Scholar the of IFN signaling is in macrophages with by their for to physiological On recognition of a is for macrophages to macrophage activity and N. 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