Pulmonary epithelial cell responses can enhance type 2 immunity and contribute to control of nematode infections. An important epithelial product is the collectin Surfactant Protein D (SP-D). We found that SP-D concentrations increased in the lung following Nippostrongylus brasiliensis infection; this increase was dependent on key components of the type 2 immune response. We carried out loss and gain of function studies of SP-D to establish if SP-D was required for optimal immunity to the parasite. N. brasiliensis infection of SP-D-/- mice resulted in profound impairment of host innate immunity and ability to resolve infection. Raising pulmonary SP-D levels prior to infection enhanced parasite expulsion and type 2 immune responses, including increased numbers of IL-13 producing type 2 innate lymphoid cells (ILC2), elevated expression of markers of alternative activation by alveolar macrophages (alvM) and increased production of the type 2 cytokines IL-4 and IL-13. Adoptive transfer of alvM from SP-D-treated parasite infected mice into na？ve recipients enhanced immunity to N. brasiliensis. Protection was associated with selective binding by the SP-D carbohydrate recognition domain (CRD) to L4 parasites to enhance their killing by alvM. These findings are the first demonstration that the collectin SP-D is an essential component of host innate immunity to helminths.
References
[1]
Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5(1):58–68. Epub 2005/01/05. doi: nri1528 [pii] doi: 10.1038/nri1528 pmid:15630429.
[2]
Madsen J, Kliem A, Tornoe I, Skjodt K, Koch C, Holmskov U. Localization of lung surfactant protein D on mucosal surfaces in human tissues. J Immunol. 2000;164(11):5866–70. Epub 2000/05/23. doi: ji_v164n10p5866 [pii]. pmid:10820266. doi: 10.4049/jimmunol.164.11.5866
[3]
Hasegawa Y, Takahashi M, Ariki S, Asakawa D, Tajiri M, Wada Y, et al. Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling. Oncogene. 2014. Epub 2014/03/13. doi: 10.1038/onc.2014.20 onc201420 [pii]. pmid:24608429.
[4]
Yoshida M, Whitsett JA. Alveolar macrophages and emphysema in surfactant protein-D-deficient mice. Respirology. 2006;11 Suppl:S37–40. doi: 10.1111/j.1440-1843.2006.00806.x pmid:16423269.
[5]
Clark H, Palaniyar N, Hawgood S, Reid KB. A recombinant fragment of human surfactant protein D reduces alveolar macrophage apoptosis and pro-inflammatory cytokines in mice developing pulmonary emphysema. Ann N Y Acad Sci. 2003;1010:113–6. Epub 2004/03/23. pmid:15033705. doi: 10.1196/annals.1299.019
[6]
Strong P, Reid KB, Clark H. Intranasal delivery of a truncated recombinant human SP-D is effective at down-regulating allergic hypersensitivity in mice sensitized to allergens of Aspergillus fumigatus. Clin Exp Immunol. 2002;130(1):19–24. Epub 2002/09/26. doi: 1968 [pii]. pmid:12296848. doi: 10.1046/j.1365-2249.2002.01968.x
[7]
Strong P, Townsend P, Mackay R, Reid KB, Clark HW. A recombinant fragment of human SP-D reduces allergic responses in mice sensitized to house dust mite allergens. Clin Exp Immunol. 2003;134(2):181–7. Epub 2003/11/18. doi: 2281 [pii]. pmid:14616775. doi: 10.1046/j.1365-2249.2003.02281.x
[8]
Yasuda K, Muto T, Kawagoe T, Matsumoto M, Sasaki Y, Matsushita K, et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci U S A. 2012;109(9):3451–6. Epub 2012/02/15. doi: 10.1073/pnas.1201042109 1201042109 [pii]. pmid:22331917.
[9]
Haczku A, Cao Y, Vass G, Kierstein S, Nath P, Atochina-Vasserman EN, et al. IL-4 and IL-13 form a negative feedback circuit with surfactant protein-D in the allergic airway response. Journal of immunology. 2006;176(6):3557–65. pmid:16517724. doi: 10.4049/jimmunol.176.6.3557
[10]
Chen F, Liu Z, Wu W, Rozo C, Bowdridge S, Millman A, et al. An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med. 2012;18(2):260–6. Epub 2012/01/17. doi: 10.1038/nm.2628 nm.2628 [pii]. pmid:22245779.
[11]
Aono Y, Ledford JG, Mukherjee S, Ogawa H, Nishioka Y, Sone S, et al. Surfactant protein-D regulates effector cell function and fibrotic lung remodeling in response to bleomycin injury. Am J Respir Crit Care Med. 2012;185(5):525–36. Epub 2011/12/27. doi: 10.1164/rccm.201103-0561OC rccm.201103-0561OC [pii]. pmid:22198976.
[12]
Allen JE, Wynn TA. Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog. 2011;7(5):e1002003. Epub 2011/05/19. doi: 10.1371/journal.ppat.1002003 PPATHOGENS-D-10-00186 [pii]. pmid:21589896.
[13]
Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol. 2013;13(8):607–14. Epub 2013/07/06. doi: 10.1038/nri3476 nri3476 [pii]. pmid:23827958.
[14]
Maizels RM, Hewitson JP, Smith KA. Susceptibility and immunity to helminth parasites. Curr Opin Immunol. 2012;24(4):459–66. Epub 2012/07/17. doi: 10.1016/j.coi.2012.06.003 S0952-7915(12)00096-9 [pii]. pmid:22795966.
[15]
Smith KA, Filbey KJ, Reynolds LA, Hewitson JP, Harcus Y, Boon L, et al. Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths. Mucosal Immunol. 2015. doi: 10.1038/mi.2015.73 pmid:26286232.
[16]
Ritter M, Gross O, Kays S, Ruland J, Nimmerjahn F, Saijo S, et al. Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses. Proc Natl Acad Sci U S A. 2010;107(47):20459–64. doi: 10.1073/pnas.1010337107 pmid:21059925; PubMed Central PMCID: PMC2996650.
[17]
van de Wetering JK, van Remoortere A, Vaandrager AB, Batenburg JJ, van Golde LM, Hokke CH, et al. Surfactant protein D binding to terminal alpha1-3-linked fucose residues and to Schistosoma mansoni. Am J Respir Cell Mol Biol. 2004;31(5):565–72. Epub 2004/07/31. doi: 10.1165/rcmb.2004-0105OC 2004-0105OC [pii]. pmid:15284077.
[18]
Thawer SG, Horsnell WG, Darby M, Hoving JC, Dewals B, Cutler AJ, et al. Lung-resident CD4 T cells are sufficient for IL-4Ralpha-dependent recall immunity to Nippostrongylus brasiliensis infection. Mucosal Immunol. 2013. Epub 2013/06/20. doi: 10.1038/mi.2013.40 mi201340 [pii]. pmid:23778354.
[19]
Harvie M, Camberis M, Tang SC, Delahunt B, Paul W, Le Gros G. The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites. Infect Immun. 2010;78(9):3753–62. Epub 2010/07/08. doi: 10.1128/IAI.00502-09 IAI.00502-09 [pii]. pmid:20605978.
[20]
Horsnell WG, Darby MG, Hoving JC, Nieuwenhuizen N, McSorley HJ, Ndlovu H, et al. IL-4Ralpha-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection. PLoS Pathog. 2013;9(10):e1003662. Epub 2013/11/10. doi: 10.1371/journal.ppat.1003662 PPATHOGENS-D-12-03060 [pii]. pmid:24204255.
[21]
Zhang L, Ikegami M, Dey CR, Korfhagen TR, Whitsett JA. Reversibility of pulmonary abnormalities by conditional replacement of surfactant protein D (SP-D) in vivo. The Journal of biological chemistry. 2002;277(41):38709–13. doi: 10.1074/jbc.M206200200 pmid:12163500.
[22]
Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–70. Epub 2010/03/05. doi: 10.1038/nature08900 nature08900 [pii]. pmid:20200518.
[23]
Gardai SJ, Xiao YQ, Dickinson M, Nick JA, Voelker DR, Greene KE, et al. By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell. 2003;115(1):13–23. Epub 2003/10/09. doi: S009286740300758X [pii]. pmid:14531999. doi: 10.1016/s0092-8674(03)00758-x
[24]
Janssen WJ, McPhillips KA, Dickinson MG, Linderman DJ, Morimoto K, Xiao YQ, et al. Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRP alpha. Am J Respir Crit Care Med. 2008;178(2):158–67. Epub 2008/04/19. doi: 10.1164/rccm.200711-1661OC 200711-1661OC [pii]. pmid:18420961.
[25]
Atochina-Vasserman EN, Guo CJ, Abramova E, Golden TN, Sims M, James ML, et al. Surfactant Dysfunction and Lung Inflammation in the Female Mouse Model of Lymphangioleiomyomatosis (LAM). American journal of respiratory cell and molecular biology. 2014. doi: 10.1165/rcmb.2014-0224OC pmid:25474372.
[26]
Groves AM, Gow AJ, Massa CB, Hall L, Laskin JD, Laskin DL. Age-related increases in ozone-induced injury and altered pulmonary mechanics in mice with progressive lung inflammation. American journal of physiology Lung cellular and molecular physiology. 2013;305(8):L555–68. doi: 10.1152/ajplung.00027.2013 pmid:23997172; PubMed Central PMCID: PMC3798776.
[27]
Chen F, Wu W, Millman A, Craft JF, Chen E, Patel N, et al. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat Immunol. 2014;15(10):938–46. doi: 10.1038/ni.2984 pmid:25173346.
[28]
Anthony RM, Urban JF Jr., Alem F, Hamed HA, Rozo CT, Boucher JL, et al. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med. 2006;12(8):955–60. Epub 2006/08/08. doi: nm1451 [pii] doi: 10.1038/nm1451 pmid:16892038.
[29]
Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A, Radwanska M, et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity. 2004;20(5):623–35. Epub 2004/05/15. doi: S1074761304001074 [pii]. pmid:15142530. doi: 10.1016/s1074-7613(04)00107-4
[30]
Horsnell WG, Brombacher F. Genes associated with alternatively activated macrophages discretely regulate helminth infection and pathogenesis in experimental mouse models. Immunobiology. 2010;215(9–10):704–8. Epub 2010/07/03. doi: 10.1016/j.imbio.2010.05.011 S0171-2985(10)00077-X [pii]. pmid:20594611.
[31]
Clark H, Reid KB. Structural requirements for SP-D function in vitro and in vivo: therapeutic potential of recombinant SP-D. Immunobiology. 2002;205(4–5):619–31. Epub 2002/10/25. doi: S0171-2985(04)70108-4 [pii] doi: 10.1078/0171-2985-00159 pmid:12396020.
[32]
McIntosh JC, Swyers AH, Fisher JH, Wright JR. Surfactant proteins A and D increase in response to intratracheal lipopolysaccharide. Am J Respir Cell Mol Biol. 1996;15(4):509–19. Epub 1996/10/01. doi: 10.1165/ajrcmb.15.4.8879185 pmid:8879185.
[33]
Fujita M, Shannon JM, Ouchi H, Voelker DR, Nakanishi Y, Mason RJ. Serum surfactant protein D is increased in acute and chronic inflammation in mice. Cytokine. 2005;31(1):25–33. doi: 10.1016/j.cyto.2005.02.006 pmid:15967375.
[34]
Kasper M, Sims G, Koslowski R, Kuss H, Thuemmler M, Fehrenbach H, et al. Increased surfactant protein D in rat airway goblet and Clara cells during ovalbumin-induced allergic airway inflammation. Clin Exp Allergy. 2002;32(8):1251–8. pmid:12190667. doi: 10.1046/j.1365-2745.2002.01423.x
[35]
Haczku A, Atochina EN, Tomer Y, Chen H, Scanlon ST, Russo S, et al. Aspergillus fumigatus-induced allergic airway inflammation alters surfactant homeostasis and lung function in BALB/c mice. American journal of respiratory cell and molecular biology. 2001;25(1):45–50. doi: 10.1165/ajrcmb.25.1.4391 pmid:11472974.
[36]
Soerensen CM, Holmskov U, Aalbaek B, Boye M, Heegaard PM, Nielsen OL. Pulmonary infections in swine induce altered porcine surfactant protein D expression and localization to dendritic cells in bronchial-associated lymphoid tissue. Immunology. 2005;115(4):526–35. doi: 10.1111/j.1365-2567.2005.02189.x pmid:16011521; PubMed Central PMCID: PMCPMC1782188.
[37]
Urban JF Jr., Noben-Trauth N, Donaldson DD, Madden KB, Morris SC, Collins M, et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity. 1998;8(2):255–64. pmid:9492006. doi: 10.1016/s1074-7613(00)80477-x
[38]
Kingma PS, Whitsett JA. In defense of the lung: surfactant protein A and surfactant protein D. Curr Opin Pharmacol. 2006;6(3):277–83. doi: 10.1016/j.coph.2006.02.003 pmid:16580255.
[39]
LeVine AM, Whitsett JA. Pulmonary collectins and innate host defense of the lung. Microbes Infect. 2001;3(2):161–6. pmid:11251302. doi: 10.1016/s1286-4579(00)01363-0
[40]
Clark H, Palaniyar N, Strong P, Edmondson J, Hawgood S, Reid KB. Surfactant protein D reduces alveolar macrophage apoptosis in vivo. J Immunol. 2002;169(6):2892–9. Epub 2002/09/10. pmid:12218102. doi: 10.4049/jimmunol.169.6.2892
[41]
Nair MG, Du Y, Perrigoue JG, Zaph C, Taylor JJ, Goldschmidt M, et al. Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung. J Exp Med. 2009;206(4):937–52. doi: 10.1084/jem.20082048 pmid:19349464; PubMed Central PMCID: PMCPMC2715126.
[42]
Herbert DR, Yang JQ, Hogan SP, Groschwitz K, Khodoun M, Munitz A, et al. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med. 2009;206(13):2947–57. Epub 2009/12/10. doi: 10.1084/jem.20091268 jem.20091268 [pii]. pmid:19995957.
[43]
Wills-Karp M, Rani R, Dienger K, Lewkowich I, Fox JG, Perkins C, et al. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med. 2012;209(3):607–22. Epub 2012/02/15. doi: 10.1084/jem.20110079 jem.20110079 [pii]. pmid:22329990.
[44]
Massacand JC, Stettler RC, Meier R, Humphreys NE, Grencis RK, Marsland BJ, et al. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc Natl Acad Sci U S A. 2009;106(33):13968–73. Epub 2009/08/12. doi: 10.1073/pnas.0906367106 0906367106 [pii]. pmid:19666528.
[45]
McKenzie GJ, Fallon PG, Emson CL, Grencis RK, McKenzie AN. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J Exp Med. 1999;189(10):1565–72. Epub 1999/05/20. pmid:10330435. doi: 10.1084/jem.189.10.1565
[46]
Mohrs M, Holscher C, Brombacher F. Interleukin-4 receptor alpha-deficient BALB/c mice show an unimpaired T helper 2 polarization in response to Leishmania major infection. Infect Immun. 2000;68(4):1773–80. Epub 2000/03/18. pmid:10722563. doi: 10.1128/iai.68.4.1773-1780.2000
[47]
Korfhagen TR, Sheftelyevich V, Burhans MS, Bruno MD, Ross GF, Wert SE, et al. Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo. The Journal of biological chemistry. 1998;273(43):28438–43. pmid:9774472. doi: 10.1074/jbc.273.43.28438
[48]
Horsnell WG, Cutler AJ, Hoving JC, Mearns H, Myburgh E, Arendse B, et al. Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice. PLoS Pathog. 2007;3(1):e1. Epub 2007/01/16. doi: 06-PLPA-RA-0111R2 [pii] doi: 10.1371/journal.ppat.0030001 pmid:17222057.
