Host control of influenza A virus (IAV) is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs). It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, we demonstrate that in addition to its known anti-viral activity, STAT1 signaling coordinates host inflammation during IAV infection in mice. This regulatory mechanism is dependent on both type I IFN and IFN-γ receptor signaling and, importantly, requires the functional interplay between the two pathways. The protective function of type I IFNs is associated with not only the recruitment of classical inflammatory Ly6Chi monocytes into IAV-infected lungs, but also the prevention of excessive monocyte activation by IFN-γ. Unexpectedly, type I IFNs preferentially regulate IFN-γ signaling in Ly6Clo rather than inflammatory Ly6Chi mononuclear cell populations. In the absence of type I IFN signaling, Ly6Clo monocytes/macrophages, become phenotypically and functionally more proinflammatory than Ly6Chi cells, revealing an unanticipated function of the Ly6Clo mononuclear cell subset in tissue inflammation. In addition, we show that type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking. Type I IFN signaling is necessary, but not sufficient, for preventing neutrophil recruitment into the lungs of IAV-infected mice. Instead, the cooperation of type I IFNs and lymphocyte-produced IFN-γ is required to regulate the tissue neutrophilic response to IAV. Our study demonstrates that IFN interplay links innate and adaptive anti-viral immunity to orchestrate tissue inflammation and reveals an additional level of complexity for IFN-dependent regulatory mechanisms that function to prevent excessive immunopathology while preserving anti-microbial functions.
References
[1]
Braciale TJ, Sun J, Kim TS (2012) Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol 12: 295–305. doi: 10.1038/nri3166. pmid:22402670
[2]
Iwasaki A, Pillai PS (2014) Innate immunity to influenza virus infection. Nat Rev Immunol 14: 315–328. doi: 10.1038/nri3665. pmid:24762827
[3]
Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, et al. (2007) Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445: 319–323. pmid:17230189 doi: 10.1038/nature05495
[4]
Kash JC, Basler CF, Garcia-Sastre A, Carter V, Billharz R, et al. (2004) Global host immune response: pathogenesis and transcriptional profiling of type A influenza viruses expressing the hemagglutinin and neuraminidase genes from the 1918 pandemic virus. J Virol 78: 9499–9511. pmid:15308742 doi: 10.1128/jvi.78.17.9499-9511.2004
[5]
Kash JC, Tumpey TM, Proll SC, Carter V, Perwitasari O, et al. (2006) Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443: 578–581. pmid:17006449 doi: 10.1038/nature05181
[6]
La Gruta NL, Kedzierska K, Stambas J, Doherty PC (2007) A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol 85: 85–92. pmid:17213831 doi: 10.1038/sj.icb.7100026
[7]
Brandes M, Klauschen F, Kuchen S, Germain RN (2013) A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell 154: 197–212. doi: 10.1016/j.cell.2013.06.013. pmid:23827683
[8]
Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, et al. (2011) Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol 179: 199–210. doi: 10.1016/j.ajpath.2011.03.013. pmid:21703402
[9]
Narasaraju T, Ng HH, Phoon MC, Chow VT (2010) MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. Am J Respir Cell Mol Biol 42: 732–743. doi: 10.1165/rcmb.2008-0423OC. pmid:19617401
[10]
Lin KL, Suzuki Y, Nakano H, Ramsburg E, Gunn MD (2008) CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol 180: 2562–2572. pmid:18250467 doi: 10.4049/jimmunol.180.4.2562
[11]
Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, et al. (2010) Development of monocytes, macrophages, and dendritic cells. Science 327: 656–661. doi: 10.1126/science.1178331. pmid:20133564
[12]
Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11: 762–774. doi: 10.1038/nri3070. pmid:21984070
[13]
Aldridge JR Jr., Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, et al. (2009) TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci U S A 106: 5306–5311. doi: 10.1073/pnas.0900655106. pmid:19279209
[14]
Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27: 669–692. doi: 10.1146/annurev.immunol.021908.132557. pmid:19132917
[15]
Pestka S (2007) The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 282: 20047–20051. pmid:17502369 doi: 10.1074/jbc.r700004200
[16]
Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. Journal of leukocyte biology 75: 163–189. pmid:14525967 doi: 10.1189/jlb.0603252
[17]
Seo SU, Kwon HJ, Ko HJ, Byun YH, Seong BL, et al. (2011) Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice. PLoS Pathog 7: e1001304. doi: 10.1371/journal.ppat.1001304. pmid:21383977
[18]
Lin SJ, Lo M, Kuo RL, Shih SR, Ojcius DM, et al. (2014) The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection. J Biomed Sci 21: 99. doi: 10.1186/s12929-014-0099-6. pmid:25407417
[19]
Marois I, Cloutier A, Garneau E, Richter MV (2012) Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract. J Leukoc Biol 92: 107–121. doi: 10.1189/jlb.1011490. pmid:22504848
[20]
Garcia-Sastre A, Durbin RK, Zheng H, Palese P, Gertner R, et al. (1998) The role of interferon in influenza virus tissue tropism. J Virol 72: 8550–8558. pmid:9765393
[21]
Durbin JE, Fernandez-Sesma A, Lee CK, Rao TD, Frey AB, et al. (2000) Type I IFN modulates innate and specific antiviral immunity. J Immunol 164: 4220–4228. pmid:10754318 doi: 10.4049/jimmunol.164.8.4220
[22]
Essers MAG, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, et al. (2009) IFN alpha activates dormant haematopoietic stem cells in vivo. Nature 458: 904–U911. doi: 10.1038/nature07815. pmid:19212321
[23]
Oguro H, Ding L, Morrison SJ (2013) SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell 13: 102–116. doi: 10.1016/j.stem.2013.05.014. pmid:23827712
[24]
Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, et al. (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317: 666–670. pmid:17673663 doi: 10.1126/science.1142883
[25]
Antonelli LR, Gigliotti Rothfuchs A, Goncalves R, Roffe E, Cheever AW, et al. (2010) Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J Clin Invest 120: 1674–1682. doi: 10.1172/JCI40817. pmid:20389020
[26]
Rayamajhi M, Humann J, Penheiter K, Andreasen K, Lenz LL (2010) Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma. J Exp Med 207: 327–337. doi: 10.1084/jem.20091746. pmid:20123961
[27]
Kearney SJ, Delgado C, Eshleman EM, Hill KK, O'Connor BP, et al. (2013) Type I IFNs downregulate myeloid cell IFN-gamma receptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription. J Immunol 191: 3384–3392. doi: 10.4049/jimmunol.1203510. pmid:23935197
[28]
Silvennoinen O, Schindler C, Schlessinger J, Levy DE (1993) Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science 261: 1736–1739. pmid:8378775 doi: 10.1126/science.8378775
[29]
Lee CK, Gimeno R, Levy DE (1999) Differential regulation of constitutive major histocompatibility complex class I expression in T and B lymphocytes. J Exp Med 190: 1451–1464. pmid:10562320 doi: 10.1084/jem.190.10.1451
[30]
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334 (Pt 2): 297–314. pmid:9716487 doi: 10.1042/bj3340297
[31]
Stock AT, Smith JM, Carbone FR (2014) Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection. J Exp Med 211: 751–759. doi: 10.1084/jem.20132183. pmid:24752295
[32]
Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14: 778–809, table of contents. pmid:11585785 doi: 10.1128/cmr.14.4.778-809.2001
[33]
Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, et al. (2015) Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J Exp Med 212: 699–714. doi: 10.1084/jem.20140825. pmid:25897172
[34]
Wareing MD, Lyon A, Inglis C, Giannoni F, Charo I, et al. (2007) Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2-/- mice. J Leukoc Biol 81: 793–801. pmid:17179466 doi: 10.1189/jlb.0506299
[35]
Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N (2000) Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol 156: 1951–1959. pmid:10854218 doi: 10.1016/s0002-9440(10)65068-7
[36]
Lee PY, Li Y, Kumagai Y, Xu Y, Weinstein JS, et al. (2009) Type I interferon modulates monocyte recruitment and maturation in chronic inflammation. Am J Pathol 175: 2023–2033. doi: 10.2353/ajpath.2009.090328. pmid:19808647
[37]
Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, et al. (2011) The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol 12: 778–785. doi: 10.1038/ni.2063. pmid:21725321
[38]
Yona S, Kim KW, Wolf Y, Mildner A, Varol D, et al. (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38: 79–91. doi: 10.1016/j.immuni.2012.12.001. pmid:23273845
[39]
Hermesh T, Moltedo B, Moran TM, Lopez CB (2010) Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe 7: 343–353. doi: 10.1016/j.chom.2010.04.006. pmid:20478536
[40]
Graham MB, Dalton DK, Giltinan D, Braciale VL, Stewart TA, et al. (1993) Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med 178: 1725–1732. pmid:8228818 doi: 10.1084/jem.178.5.1725
[41]
Price GE, Gaszewska-Mastarlarz A, Moskophidis D (2000) The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice. J Virol 74: 3996–4003. pmid:10756011 doi: 10.1128/jvi.74.9.3996-4003.2000
[42]
Nguyen HH, van Ginkel FW, Vu HL, Novak MJ, McGhee JR, et al. (2000) Gamma interferon is not required for mucosal cytotoxic T-lymphocyte responses or heterosubtypic immunity to influenza A virus infection in mice. J Virol 74: 5495–5501. pmid:10823854 doi: 10.1128/jvi.74.12.5495-5501.2000
[43]
Blazek K, Eames HL, Weiss M, Byrne AJ, Perocheau D, et al. (2015) IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1beta production. J Exp Med 212: 845–853. doi: 10.1084/jem.20140995. pmid:25941255
[44]
Mordstein M, Kochs G, Dumoutier L, Renauld JC, Paludan SR, et al. (2008) Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog 4: e1000151. doi: 10.1371/journal.ppat.1000151. pmid:18787692
[45]
Wack A, Terczynska-Dyla E, Hartmann R (2015) Guarding the frontiers: the biology of type III interferons. Nat Immunol 16: 802–809. doi: 10.1038/ni.3212. pmid:26194286
[46]
Lazear HM, Nice TJ, Diamond MS (2015) Interferon-lambda: Immune Functions at Barrier Surfaces and Beyond. Immunity 43: 15–28. doi: 10.1016/j.immuni.2015.07.001. pmid:26200010
[47]
Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32: 593–604. doi: 10.1016/j.immuni.2010.05.007. pmid:20510870
[48]
Stifter SA, Feng CG (2015) Interfering with immunity: detrimental role of type I IFNs during infection. J Immunol 194: 2455–2465. doi: 10.4049/jimmunol.1402794. pmid:25747907
[49]
Karupiah G, Chen JH, Mahalingam S, Nathan CF, MacMicking JD (1998) Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. J Exp Med 188: 1541–1546. pmid:9782132 doi: 10.1084/jem.188.8.1541
[50]
Akaike T, Noguchi Y, Ijiri S, Setoguchi K, Suga M, et al. (1996) Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci U S A 93: 2448–2453. pmid:8637894 doi: 10.1073/pnas.93.6.2448
[51]
Perrone LA, Belser JA, Wadford DA, Katz JM, Tumpey TM (2013) Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice. J Infect Dis 207: 1576–1584. doi: 10.1093/infdis/jit062. pmid:23420903
[52]
Garcia-Sastre A, Biron CA (2006) Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312: 879–882. pmid:16690858 doi: 10.1126/science.1125676
[53]
Kochs G, Garcia-Sastre A, Martinez-Sobrido L (2007) Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol 81: 7011–7021. pmid:17442719 doi: 10.1128/jvi.02581-06
[54]
Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM (2008) H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog 4: e1000115. doi: 10.1371/journal.ppat.1000115. pmid:18670648
[55]
Cilloniz C, Shinya K, Peng X, Korth MJ, Proll SC, et al. (2009) Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes. PLoS Pathog 5: e1000604. doi: 10.1371/journal.ppat.1000604. pmid:19798428
