The regulatory landscape of macrophage interferon signaling in inflammation
2023; Elsevier BV; Volume: 152; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2023.04.022
ISSN1097-6825
AutoresRicky Siebeler, Menno P.J. de Winther, Marten A. Hoeksema,
Tópico(s)Immune cells in cancer
ResumoThe 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 human autoimmunity.Nat Commun. 2020; 11: 1-18Crossref PubMed Scopus (10) Google Scholar, 10Yin Z. Dai J. Deng J. Sheikh F. Natalia M. Shih T. et al.Type III IFNs are produced by and stimulate human plasmacytoid dendritic cells.J Immunol. 2012; 189: 2735Crossref PubMed Scopus (137) Google Scholar, 11Schoenborn J.R. Wilson C.B. Regulation of interferon-gamma during innate and adaptive immune responses.Adv Immunol. 2007; 96: 41-101Crossref PubMed Scopus (1229) Google Scholar However, various other IFN-producing leukocytes have been identified, including macrophages,12Ali S. Mann-Nüttel R. Schulze A. Richter L. Alferink J. Scheu S. Sources of type I interferons in infectious immunity: plasmacytoid dendritic cells not always in the driver's seat.Front Immunol. 2019; 10: 778Crossref PubMed Scopus (33) Google Scholar, 13Darwich L. Coma G. Peña R. Bellido R. Blanco E.J.J. Este J.A. et al.Secretion of interferon-gamma by human macrophages demonstrated at the single-cell level after costimulation with interleukin (IL)-12 plus IL-18.Immunology. 2009; 126: 386-393Crossref PubMed Scopus (139) Google Scholar, 14Bao Y. Liu X. Han C. Xu S. Xie B. Zhang Q. et al.Identification of IFN-γ-producing innate B cells.Cell Res. 2013; 24: 161-176Crossref PubMed Scopus (94) Google Scholar, 15Nikonova A. Khaitov M. Jackson D.J. Traub S. Trujillo-Torralbo M.B. Kudlay D.A. et al.M1-like macrophages are potent producers of anti-viral interferons and M1-associated marker-positive lung macrophages are decreased during rhinovirus-induced asthma exacerbations.EBioMedicine. 2020; 54102734Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar thereby challenging the current dogma of the lone IFN producers. The dual nature of macrophages, being both tissue-resident and derived from migratory monocytes, facilitates their universal role in tissue homeostasis and immunity.16Zhang C. Yang M. Ericsson A.C. Function of macrophages in disease: current understanding on molecular mechanisms.Front Immunol. 2021; 12: 635Google Scholar Importantly, macrophages are effective mediators of immunity by taking on the role of judge, jury, and executioner in innate immune responses. Pathogen recognition receptors (PRRs) constitute a wide number of sensors macrophages use to judge environmental exposures, such as pathogen-associated molecular patterns (PAMPs). The main PRRs to consider for IFN responses are transmembrane receptors such as Toll-like receptors (TLRs) and cytosolic receptors such as retinoic acid–inducible gene 1 (RIG-I) and melanoma differentiation–associated gene 5 (MDA5). Macrophages use their repertoire of PRRs and mediators to discriminate between intracellular versus extracellular pathogens, viral versus bacterial, and endogenous versus exogenous exposures, effectively enabling macrophages to execute an appropriate set of actions in response to their environment, including the propagation of an IFN response. Apart from secreting IFNs, macrophages are responsive to IFNs, placing them in the center of the IFN system.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,12Ali S. Mann-Nüttel R. Schulze A. Richter L. Alferink J. Scheu S. Sources of type I interferons in infectious immunity: plasmacytoid dendritic cells not always in the driver's seat.Front Immunol. 2019; 10: 778Crossref PubMed Scopus (33) Google Scholar Yet, this central role also implicates macrophages in interferonopathies.17Chen H.J. Tas S.W. de Winther M.P.J. Type-I interferons in atherosclerosis.J Exp Med. 2020; 217e20190459Crossref Scopus (39) Google Scholar,18Moulton V.R. Suarez-Fueyo A. Meidan E. Li H. Mizui M. Tsokos G.C. Pathogenesis of human systemic lupus erythematosus: a cellular perspective.Trends Mol Med. 2017; 23: 615Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar Transcriptional profiling using state-of-the-art technological advancements has allowed for the characterization of processes steering the IFN system, shedding light on delicate regulatory cascades. This review will cover the current understanding of regulatory networks underlying IFN responses in macrophages. An integral feature of IFNs is their ability to enhance cellular responsiveness to immunologic challenges. These effects were first observed more than 50 years ago and are yet to be fully elucidated.19Stewart II, W.E. Gosser L.B. Lockart Jr., R.Z. Priming: a nonantiviral function of interferon.J Virol. 1971; 7: 792Crossref PubMed Google Scholar Since then, the IFN system is established to comprise 3 classes of cytokines: type I, II, and III IFNs. There are several subclasses of type I (including IFN-α subtypes and IFN-β) and III IFNs (IFN-λ1 to 4), and a single type II IFN (IFN-γ). The evolutionary advantage of these subclasses is largely unknown, but functional differences come down to receptor affinity.20Wittling M.C. Cahalan S.R. Levenson E.A. Rabin R.L. Shared and unique features of human interferon-beta and interferon-alpha subtypes.Front Immunol. 2021; 11: 3325Crossref Scopus (22) Google Scholar,21Jaks E. Gavutis M. Uzé G. Martal J. Piehler J. Differential receptor subunit affinities of type I interferons govern differential signal activation.J Mol Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar Despite shared nomenclature, the different types of IFNs share little structural homology.22Ealick S.E. Cook W.J. Vijay-Kumar S. Carson M. Nagabhushan T.L. Trotta P.P. et al.Three-dimensional structure of recombinant human interferon-γ.Science (1979). 1991; 252: 698-702Crossref PubMed Google Scholar, 23Radhakrishnan R. Walter L.J. Hruza A. Reichert P. Trotta P.P. Nagabhushan T.L. et al.Zinc mediated dimer of human interferon-alpha 2b revealed by X-ray crystallography.Structure. 1996; 4: 1453-1463Abstract Full Text Full Text PDF PubMed Google Scholar, 24Karpusas M. Nolte M. Benton C.B. Meier W. Lipscomb W.N. Goelz S. The crystal structure of human interferon beta at 2.2-A resolution.Proc Natl Acad Sci U S A. 1997; 94: 11813-11818Crossref PubMed Scopus (0) Google Scholar Accordingly, each class of IFNs binds a different receptor, canonically eliciting distinct signaling cascades. Their commonality is their regulatory role, exerting immunomodulating effects either autocrine or paracrine (Fig 1). Biochemically, the binding of type I IFNs to IFN-α/β receptor 1 and 2 triggers conformational change, allowing tyrosine kinase 2 and Janus kinase (JAK) 1 to phosphorylate signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2), causing heterodimerization. STAT1/STAT2 recruits IFN regulatory factor 9 (IRF9) to assemble heterotrimeric transcription complex IFN-stimulated gene factor 3 (ISGF3). Distinctly, type II IFN binds IFN-γ receptor 1 and 2, leading to JAK1- and JAK2-mediated phosphorylation and homodimerization of STAT1. The newly formed transcription complex IFN-γ activation factor will canonically translocate to the nucleus to bind gamma-activated sequence promoter elements, whereas ISGF3 binds IFN-stimulated response elements (ISREs), both promoting the expression of ISGs. Type III IFNs bind a heterodimeric receptor of IFN-λ receptor 1 and IL-10 receptor beta subunit, yet share their downstream signaling pathway with type I IFNs (Fig 1). ISGs are located downstream of ISREs, mainly encoding proteins with antimicrobial properties to protect the host from pathogenic exposures. Some of the most well-characterized ISGs are oligoadenylate synthetases, IFN-induced proteins with tetratricopeptide repeats, and IFN-induced GTP-binding protein. Strikingly, IRFs are also ISGs, thus generating a positive feedback loop in the transcription of ISGs. Similarly, various PRRs are under the control of ISREs. Altogether ISGs work in concert, targeting all stages of the viral life-cycle, from entry to egress.25Schoggins J.W. Interferon-stimulated genes: what do they all do?.Annu Rev Virol. 2019; 6: 567-584Crossref PubMed Scopus (380) Google Scholar ISGs are extensively studied in viral infections, but given how studying IFNs in nonviral immunity is relatively novel, little is known about the antibacterial properties of ISGs. It is likely for ISGs to eradicate bacterial pathogens in a similar way to viral infections, by limiting conserved aspects of replication and migration.26LeMessurier K.S. Häcker H. Chi L. Tuomanen E. Redecke V. Type I interferon protects against pneumococcal invasive disease by inhibiting bacterial transmigration across the lung.PLoS Pathog. 2013; 9e1003727Crossref PubMed Scopus (65) Google Scholar, 27Helbig K.J. Teh M.Y. Crosse K.M. Monson E.A. Smith M. Tran E.N. et al.The interferon stimulated gene viperin, restricts Shigella flexneri in vitro.Sci Rep. 2019; 9: 1-12Crossref PubMed Scopus (15) Google Scholar, 28Alphonse N. Wanford J.J. Voak A.A. Gay J. Venkhaya S. Burroughs O. et al.A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling.Cell. 2022; 185: 2354-2369.e17Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 29Kumaran Satyanarayanan S. El Kebir D. Soboh S. Butenko S. Sekheri M. Saadi J. et al.IFN-β is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation.Nat Commun. 2019; 10: 3471Crossref PubMed Scopus (71) Google Scholar Importantly, IFNs contribute to monocyte mobilization by stimulating the secretion of chemokines, including C-C motif ligand 5 and C-X-C motif chemokine ligand 10.30Lee A.J. Chen B. Chew M.V. Barra N.G. Shenouda M.M. Nham T. et al.Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection.J Exp Med. 2017; 214: 1153Crossref PubMed Scopus (60) Google Scholar,31Yarilina A. Park-Min K.H. Antoniv T. Hu X. Ivashkiv L.B. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes.Nat Immunol. 2008; 9: 378-387Crossref PubMed Scopus (328) Google Scholar Similarly, IFNs serve as upstream determinants of inflammatory responses, mediating the inflammatory IL-12 response of monocytes.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 IL-12 is a potent inflammatory cytokine requiring negative regulation by the anti-inflammatory cytokine IL-10.32McNab F.W. Ewbank J. Howes A. Moreira-Teixeira L. Martirosyan A. Ghilardi N. et al.Type I IFN induces IL-10 production in an IL-27–independent manner and blocks responsiveness to IFN-γ for production of IL-12 and bacterial killing in Mycobacterium tuberculosis–infected macrophages.J Immunol. 2014; 193: 3600-3612Crossref PubMed Scopus (0) Google Scholar Interestingly, IL-10 secretion is regulated by an autocrine and paracrine type I IFN loop. On sensing LPS (a bacterial cell wall component), macrophages will unleash an inflammatory response, including the secretion of IFNs. The type I IFNs sequentially upregulate the macrophage's ability to produce IL-10, thereby resolving bacterial inflammation.33Ernst O. Glucksam-Galnoy Y. Bhatta B. Athamna M. Ben-Dror I. Glick Y. et al.Exclusive temporal stimulation of IL-10 expression in LPS-stimulated mouse macrophages by cAMP inducers and type I interferons.Front Immunol. 2019; 10: 1788Crossref PubMed Scopus (18) Google Scholar,34Ernst O. Glucksam-Galnoy Y. Athamna M. Ben-Dror I. Ben-Arosh H. Levy-Rimler G. et al.The cAMP pathway amplifies early MyD88-dependent and type i interferon-independent LPS-induced interleukin-10 expression in mouse macrophages.Mediators Inflamm. 2019; 20193451461Crossref PubMed Scopus (9) Google Scholar These findings suggest type I IFNs to form a regulatory circuit able to reprogram macrophages to promote both inflammation and resolution. Despite the ability of type II IFN to induce antiviral responses, it is a notorious activator of macrophages by enhancing the expression of macrophage signature genes containing gamma-activated sequence promotor elements in their promotors or enhancers (Fig 1). Perhaps the most well-established effect of type II IFN is the enhancement of antigen presentation through MHC-II, enabling macrophages to recruit the adaptive arm of immunity.35Eiz-Vesper B. Schmetzer H.M. Antigen-presenting cells: potential of proven and new players in immune therapies.Transf Med Hemother. 2020; 47: 429-431Crossref PubMed Scopus (14) Google Scholar Similarly, type II IFN supports the clearance of microbials by boosting core immunologic properties of the macrophage, such as phagocytosis and secretion of inflammatory cytokines, nitric oxide, and reactive oxygen species.36Kak G. Raza M. Tiwari B.K. Interferon-gamma (IFN-γ): exploring its implications in infectious diseases.Biomol Concepts. 2018; 9: 64-79Crossref PubMed Scopus (248) Google Scholar The significance of type II IFN to the macrophage's phenotype is demonstrated by its ability to differentiate monocytes to inflammatory macrophages, even in absence of M-CSF.37Luque-Martin R. Angell D.C. Kalxdorf M. Bernard S. Thompson W. Eberl H.C. et al.IFN-γ drives human monocyte differentiation into highly proinflammatory macrophages that resemble a phenotype relevant to psoriasis.J Immunol. 2021; 207: 555-568Crossref PubMed Scopus (8) Google Scholar Thereby, the type I and II IFN pathways are distinct. Still, type I and II IFN signaling have been shown to overlap. These effects are partially explained by the ability of type I IFNs to also form STAT1 homodimers, and type II IFN to signal via ISGF3,38Mazewski C. Perez R.E. Fish E.N. Platanias L.C. Type I interferon (IFN)-regulated activation of canonical and non-canonical signaling pathways.Front Immunol. 2020; 11: 3025Crossref Scopus (56) Google Scholar, 39Kok F. Rosenblatt M. Teusel M. Nizharadze T. Magalhães V.G. Dächert C. et al.Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.Mol Syst Biol. 2020; 16: e8955Crossref PubMed Scopus (5) Google Scholar, 40Platanitis E. Demiroz D. Schneller A. Fischer K. Capelle C. Hartl M. et al.A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription.Nat Commun. 2019; 10: 1-17Crossref PubMed Scopus (85) Google Scholar effectively enabling IFNs to tread into the pathways of other types of IFNs, causing substantial overlap in the cellular response to different types of IFNs. These effects are especially apparent in macrophages lacking STAT2 or IRF9, disabling the formation of ISGF3.41Gothe F. Stremenova Spegarova J. Hatton C.F. Griffin H. Sargent T. Cowley S.A. et al.Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency.J Allergy Clin Immunol. 2022; 150: 955-964.e16Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar When the ISGF3 complex is disrupted, macrophages show a gene expression signature more commonly associated with type II IFN stimulation. As to type III IFNs, first discovered in 2003, they form the most recent addition to the IFN system.42Galani I.E. Triantafyllia V. Eleminiadou E.E. Koltsida O. Stavropoulos A. Manioudaki M. et al.Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness.Immunity. 2017; 46: 875-890.e6Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar,43Kotenko S.V. Gallagher G. Baurin V.V. Lewis-Antes A. Shen M. Shah N.K. et al.IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat Immunol. 2003; 4: 69-77Crossref PubMed Scopus (1554) Google Scholar Investigative efforts are directed toward understanding the additive value of type III IFNs over a more rudimentary IFN system featuring only type I and type II IFNs. Current leads suggest a local tissue-specific and first-responder role of type III IFNs, whereas type I IFNs induce a strong systemic immune response.42Galani I.E. Triantafyllia V. Eleminiadou E.E. Koltsida O. Stavropoulos A. Manioudaki M. et al.Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness.Immunity. 2017; 46: 875-890.e6Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar,44Contoli M. Message S.D. Laza-Stanca V. Edwards M.R. Wark P.A.B. Bartlett N.W. et al.Role of deficient type III interferon-lambda production in asthma exacerbations.Nat Med. 2006; 12: 1023-1026Crossref PubMed Scopus (872) Google Scholar, 45Wack A. Terczyńska-Dyla E. Hartmann R. Guarding the frontiers: the biology of type III interferons.Nat Immunol. 2015; 16: 802-809Crossref PubMed Scopus (231) Google Scholar, 46Ye L. Schnepf D. Staeheli P. Interferon-λ orchestrates innate and adaptive mucosal immune responses.Nat Rev Immunol. 2019; 19: 614-625Crossref PubMed Scopus (136) Google Scholar, 47Lazear H.M. Schoggins J.W. Diamond M.S. Shared and distinct functions of type I and type III interferons.Immunity. 2019; 50: 907Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 48Cao Y. Huang Y. Xu K. Liu Y. Li X. Xu Y. et al.Differential responses of innate immunity triggered by different subtypes of influenza a viruses in human and avian hosts.BMC Med Genomics. 2017; 10: 70Crossref PubMed Scopus (24) Google Scholar Combined with the individual kinetics of IFN subtypes, these findings may account for the biological relevance of the immune system to have various types and subtypes of IFNs at its disposal.21Jaks E. Gavutis M. Uzé G. Martal J. Piehler J. Differential receptor subunit affinities of type I interferons govern differential signal activation.J Mol Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar An obstacle to studying IFN signatures is the potency of IFNs. Minute quantities of type I IFN, below the detection threshold of common assays, can have a significant influence on IFN signatures.49Willemsen L. Chen H.J. Roomen CPAA van Griffith G.R. Siebeler R. Neele A.E. et al.Monocyte and macrophage lipid accumulation results in down-regulated type-I interferon responses.Front Cardiovasc Med. 2022; 9829877Crossref PubMed Scopus (4) Google Scholar This phenomenon is well illustrated by IFN signaling under homeostatic conditions, which is facilitated by low-level type I IFN secretion. One of the main roles of IFNs, in absence of environmental challenges, is to prime immune cells.50Gough D.J. Messina N.L. Clarke C.J.P. Johnstone R.W. Levy D.E. Constitutive type I interferon modulates homeostatic balance through tonic signaling.Immunity. 2012; 36: 166Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar For instance, macrophages show microbiota-driven priming by IFN, offering protection against subsequent viral infection.51Abt M.C. Osborne L.C. Monticelli L.A. Doering T.A. Alenghat T. Sonnenberg G.F. et al.Commensal bacteria calibrate the activation threshold of innate antiviral immunity.Immunity. 2012; 37: 158-170Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar, 52Wirusanti N.I. Baldridge M.T. Harris V.C. Microbiota regulation of viral infections through interferon signaling.Trends Microbiol. 2022; 30: 778-792Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This is indirectly supported by the fact that germfree mice show increased susceptibility to infections.51Abt M.C. Osborne L.C. Monticelli L.A. Doering T.A. Alenghat T. Sonnenberg G.F. et al.Commensal bacteria calibrate the activation threshold of innate antiviral immunity.Immunity. 2012; 37: 158-170Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar, 52Wirusanti N.I. Baldridge M.T. Harris V.C. Microbiota regulation of viral infections through interferon signaling.Trends Microbiol. 2022; 30: 778-792Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 53Fagundes C.T. Amaral F.A. Vieira A.T. Soares A.C. Pinho V. Nicoli J.R. et al.Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice.J Immunol. 2012; 188: 1411-1420Crossref PubMed Scopus (156) Google Scholar, 54Round J.L. Mazmanian S.K. The gut microbiome shapes intestinal immune responses during health and disease.Nat Rev Immunol. 2009; 9: 313Crossref PubMed Scopus (3388) Google Scholar Also, in IFN-reporter mice, it was shown that immunologically active tissues, such as the spleen, lymph nodes, and bone marrow, actively partake in IFN signaling in the absence of environmental challenges.55Uccellini M.B. García-Sastre A. ISRE-reporter mouse reveals high basal and induced type I IFN responses in inflammatory monocytes.Cell Rep. 2018; 25: 2784Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Basal IFN signaling was most strongly observed in monocytes, and this priming effect was shown to be critical to their antiviral responsiveness in vivo. Besides immunologic responses, myeloid-lineage cells mediate tissue homeostasis. The IFN pathway is pivotal to osteoclast differentiation and homeostasis, where IFNs mainly serve as negative feedback signals to the expression of transcription factors involved in osteoclastogenesis.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 This homeostatic role of IFN is supported by mice lacking either type I or type II IFNs, because they show reduced bone density.56Duque G. Huang D.C. Dion N. MacOritto M. Rivas D. Li W. et al.Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice.J Bone Miner Res. 2011; 26: 1472-1483Crossref PubMed Scopus (0) Google Scholar,57Salem S. Gao C. Li A. Wang H. Nguyen-Yamamoto L. Goltzman D. et al.A novel role for interferon regulatory factor 1 (IRF1) in regulation of bone metabolism.J Cell Mol Med. 2014; 18: 1588-1598Crossref PubMed Scopus (20) Google Scholar Of particular interest, reduced bone density is strongly associated with inflammatory diseases, such as SLE and rheumatoid arthritis58Bultink I.E.M. Bone disease in connective tissue disease/systemic lupus erythematosus.Calcif Tissue Int. 2018; 102: 575-591Crossref PubMed Scopus (26) Google Scholar,59Llorente I. García-Castañeda N. Valero C. González-Álvaro I. Castañeda S. Osteoporosis in rheumatoid arthritis: dangerous liaisons.Front Med (Lausanne). 2020; 7: 802Google Scholar; IFN signaling is therefore possibly adding to this pathogenic role of macrophages. More than 65 years ago, mammalian cells were first characterized to possess the inherent ability to produce IFNs, in response to viral exposures.60Isaacs A. Lindenmann J. Virus interference, I: the interferon.J Interferon Res. 1957; 7: 429-438Crossref Scopus (0) Google Scholar Moving forward, a plethora of types, roles, and producers of IFNs have been discovered.42Galani I.E. Triantafyllia V. Eleminiadou E.E. Koltsida O. Stavropoulos A. Manioudaki M. et al.Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness.Immunity. 2017; 46: 875-890.e6Abs
Referência(s)