5. CONCLUSIONS
In response to RSV infection BECs can release alarmins, mediators
effective in stimulating ILC2 to produce Th2 cytokines, promoters of
airway inflammation and hyperresponsiveness in RSV infection. Long-term
epithelial progenitors or persistent epigenetic modifications of BECs
following RSV bronchiolitis in infants, may play a pathogenetic role on
the ongoing increased susceptibility to obstructive lung diseases in
childhood. Experimental studies suggest that alarmin-induced ILC2
activation, which can be modulated by gut dysbiosis, may represent a
common pathogenetic imprint in RSV bronchiolitis and later recurrent
wheezing. A better understanding of the pathways involved in alarmin
production by airway epithelial cells and on the alarmin-ILC2
interactions might provide insights into the mechanisms characterizing
these immune-mediated diseases. The position of alarmins at the top of
the inflammatory cascade makes them a promising prevention and
therapeutic targets.
CONFLICT OF INTEREST. The author declares no conflicts of
interest.
ETHICAL APPROVAL. Because of category of the manuscript, a
review, approval from the ethical committee was not necessary.
Data availability statement. Data sharing is not applicable to
this article as no new data were created or analyzed in this manuscript.
References
- Meissner HC. Viral bronchiolitis in children. N Engl J Med
2016;374:62-72.
- Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower
respiratory infections due to respiratory syncytial virus in young
children: a systematic review and meta-analysis. Lancet 2010: 375:
1545–55.
- Rossi GA, Colin AA. Respiratory syncytial virus-Host interaction in
the pathogenesis of bronchiolitis and its impact on respiratory
morbidity in later life. Pediatr Allergy Immunol. 2017;28:320-331.
- Régnier SA, Huels J. Association between respiratory syncytial virus
hospitalizations in infants and respiratory sequelae: systematic
review and meta-analysis. Pediatr Infect Dis J. 2013;32:820-6.
- Glaser L, Coulter PJ, Shields M, Touzelet O, Power UF, Broadbent L.
Airway Epithelial Derived Cytokines and Chemokines and Their Role in
the Immune Response to Respiratory Syncytial Virus Infection.
Pathogens. 2019;8:106.
- Roan F, Obata-Ninomiya K, Ziegler SF. Epithelial cell-derived
cytokines: more than just signaling the alarm. J Clin Invest.
2019;129:1441-1451.
- Panda SK, Colonna M. Innate Lymphoid Cells in Mucosal Immunity. Front
Immunol. 2019;10:861.
- Nagakumar P, Puttur F, Gregory LG, Denney L, Fleming L, Bush A, Lloyd
CM, Saglani S. Pulmonary type-2 innate lymphoid cells in paediatric
severe asthma: phenotype and response to steroids. Eur Respir J.
2019;54:1801809
- Hsu AT, Gottschalk TA, Tsantikos E, Hibbs ML. The Role of Innate
Lymphoid Cells in Chronic Respiratory Diseases. Front Immunol.
2021;12:733324.
- Borger JG, Lau M, Hibbs ML. The Influence of Innate Lymphoid Cells and
Unconventional T Cells in Chronic Inflammatory Lung Disease. Front
Immunol. 2019;10:1597.
- Norlander AE, Peebles RS Jr. Innate Type 2 Responses to Respiratory
Syncytial Virus Infection. Viruses. 2020;12(5):521.
- Sastre B, García-García ML, Cañas JA, Calvo C, Rodrigo-Muñoz JM, Casas
I, Mahíllo-Fernández I, Del Pozo V. Bronchiolitis and recurrent
wheezing are distinguished by type 2 innate lymphoid cells and immune
response. Pediatr Allergy Immunol. 2021;32:51-59.
- Caixia L, Yang X, Yurong T, Xiaoqun Q. Involvement of epigenetic
modification in epithelial immune responses during respiratory
syncytial virus infection. Microb Pathog. 2019;130:186-189.
- Wang L, Wu G, Qin X, Ma Q, Zhou Y, Liu S, Tan Y. Expression of Nodal
on Bronchial Epithelial Cells Influenced by Lung Microbes Through DNA
Methylation Modulates the Differentiation of T-Helper Cells. Cell
Physiol Biochem. 2015;37:2012-22.
- Tan YR, Peng D, Chen CM, Qin XQ: Nonstructural protein-1 of
respiratory syncytial virus regulates HOX gene expression through
interacting with histone. Mol Biol Rep 2013;40:675-679.
- Feng Q, Su Z, Song S, Χu H, Zhang B, Yi L, Tian M, Wang H. Histone
deacetylase inhibitors suppress RSV infection and alleviate
virus-induced airway inflammation. Int J Mol Med. 2016;38:812-22.
- Xu CJ, Scheltema NM, Qi C, Vedder R, Klein LBC, Nibbelke EE, van der
Ent CK, Bont LJ, Koppelman GH. Infant RSV immunoprophylaxis changes
nasal epithelial DNA methylation at 6 years of age. Pediatr Pulmonol.
2021;56:3822-3831.
- Harding JN, Siefker D, Vu L, You D, DeVincenzo J, Pierre JF, Cormier
SA. Altered gut microbiota in infants is associated with respiratory
syncytial virus disease severity. BMC Microbiol. 2020 Jun 1;20(1):140.
- Klose CSN, Artis D. Innate lymphoid cells control signaling circuits
to regulate tissue-specific immunity. Cell Res. 2020;30:475-491.
- Willinger T. Metabolic Control of Innate Lymphoid Cell Migration.
Front Immunol. 2019 Aug 22;10:2010.
- Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, et
al. Systemic Human ILC Precursors Provide a Substrate for Tissue ILC
Differentiation. Cell. 2017; 168:1086–100.e10.
- Marashian SM, Mortaz E, Jamaati HR, Alavi-Moghaddam M, Kiani A,
Abedini A, Garssen J, Adcock IM, Velayati AA. Role of Innate Lymphoid
Cells in Lung Disease. Iran J Allergy Asthma Immunol. 2015;14:346-60.
- Spits H, Cupedo T. Innate lymphoid cells: emerging insights in
development, lineage relationships, and function. Annu Rev Immunol.
2012;30:647-75.
- Fan X, Rudensky AY. Hallmarks of Tissue-Resident Lymphocytes. Cell.
2016;164:1198-1211.
- Mjösberg J, Spits H. Human innate lymphoid cells. J Allergy Clin
Immunol. 2016;138(5):1265-1276.
- Eberl G, Colonna M, Di Santo JP, McKenzie AN (2015) Innate lymphoid
cells: a new paradigm in immunology. Science 348: aaa6566.
- Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H.
IL-33-responsive lineageCD25+CD44hi lymphoid cells mediate innate type
2 immunity and allergic inflammation in the lungs. J Immunol 2012;
188:1503–13.
- Guo L, Junttila IS, Paul WE. Cytokine-induced cytokine production by
conventional and innate lymphoid cells. Trends Immunol 2012;
33:598-606.
- Bal SM, Golebski K, Spits H. Plasticity of innate lymphoid cell
subsets. Nat Rev Immunol. 2020;20:552-565.
- Crellin NK, Trifari S, Kaplan CD, Satoh-Takayama N, Di Santo JP, Spits
H. Regulation of cytokine secretion in human CD127(+) LTi-like innate
lymphoid cells by Toll-like receptor 2. Immunity. 2010;33:752-64.
- Klein Wolterink RG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M,
Levani Y, Hendriks RW. Pulmonary innate lymphoid cells are major
producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J
Immunol. 2012;42:1106-16.
- Lambert L, Sagfors AM, Openshaw PJ, Culley FJ. Immunity to RSV in
Early-Life. Front Immunol. 2014;5:466.,
- Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its
role in the pathogenesis of asthma, and targeting it for asthma
treatment with interleukin-4 receptor antagonists. Respir Res.
2001;2:66-70.
- Cohn L, Homer RJ, Marinov A, Rankin J, Bottomly K. Induction of airway
mucus production By T helper 2 (Th2) cells: a critical role for
interleukin 4 in cell recruitment but not mucus production. J Exp Med.
1997;186:1737-47.
- Thurau AM, Streckert HJ, Rieger CH, Schauer U. Increased number of T
cells committed to IL-5 production after respiratory syncytial virus
(RSV) infection of human mononuclear cells in vitro. Clin Exp Immunol.
1998;113:450-5.
- Garofalo R, Kimpen JL, Welliver RC, Ogra PL. Eosinophil degranulation
in the respiratory tract during naturally acquired respiratory
syncytial virus infection. J Pediatr. 1992;120:28–32.
- Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA.
Pulmonary expression of interleukin-13 causes inflammation, mucus
hypersecretion, subepithelial fibrosis, physiologic abnormalities, and
eotaxin production. J Clin Invest. 1999;103:779-88.
- Webb DC, McKenzie AN, Koskinen AM, Yang M, Mattes J, Foster PS.
Integrated signals between IL-13, IL-4, and IL-5 regulate airways
hyperreactivity. J Immunol. 2000;165:108-13. 37.
- He R, Geha RS. Thymic stromal
lymphopoietin. Ann N Y Acad Sci. 2010 Jan;1183:13-24.
- Ying S, O’Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson
D, Zhang G, Zhao J, Lee TH, Corrigan C. Thymic stromal lymphopoietin
expression is increased in asthmatic airways and correlates with
expression of Th2-attracting
chemokines and disease severity. J Immunol. 2005;174:8183-90.
- García-García ML, Calvo C, Moreira A, Cañas JA, Pozo F, Sastre B,
Quevedo S, Casas I, Del Pozo V. Thymic stromal lymphopoietin, IL-33,
and periostin in hospitalized infants with viral bronchiolitis.
Medicine (Baltimore). 2017;96:e6787.
- Lee HC, Headley MB, Loo YM,
Berlin A, Gale M Jr, Debley JS, Lukacs NW, Ziegler SF. Thymic stromal
lymphopoietin is induced by respiratory syncytial virus-infected
airway epithelial cells and promotes a type 2 response to infection. J
Allergy Clin Immunol. 2012;130:1187-1196.e5
- Stier MT, Bloodworth MH, Toki S, Newcomb DC, Goleniewska K, Boyd KL,
Quitalig M, Hotard AL, Moore ML, Hartert TV, Zhou B, McKenzie AN,
Peebles RS Jr. Respiratory syncytial virus infection activates
IL-13-producing group 2 innate lymphoid cells through thymic stromal
lymphopoietin. J Allergy Clin Immunol. 2016;138:814-824.e11.
- Malinczak CA, Fonseca W, Rasky AJ, Ptaschinski C, Morris S, Ziegler
SF, Lukacs NW. Sex-associated TSLP-induced immune alterations
following early-life RSV infection leads to enhanced allergic disease.
Mucosal Immunol. 2019;12:969-979.
- Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K,
Saito H, Matsuda A. IL-33 mediates inflammatory responses in human
lung tissue cells. J Immunol. 2010;185:5743-50.
- Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, Nambu A, Abe
T, Kiyonari H, Matsumoto K, Sudo K, Okumura K, Saito H, Nakae S. IL-33
is a crucial amplifier of innate rather than acquired immunity. Proc
Natl Acad Sci U S A. 2010;107:18581-6.
- Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering
TA, Angelosanto JM, Laidlaw BJ, Yang CY, Sathaliyawala T, Kubota M,
Turner D, Diamond JM, Goldrath AW, Farber DL, Collman RG, Wherry EJ,
Artis D. Innate lymphoid cells promote lung-tissue homeostasis after
infection with influenza virus. Nat Immunol. 2011;12:1045-54.
- Liu J, Wu J, Qi F, Zeng S, Xu L, Hu H, Wang D, Liu B. Natural helper
cells contribute to pulmonary eosinophilia by producing IL-13 via
IL-33/ST2 pathway in a murine model of respiratory syncytial virus
infection. Int Immunopharmacol. 2015;28:337-43.
- Saravia J, You D, Shrestha B, Jaligama S, Siefker D, Lee GI, Harding
JN, Jones TL, Rovnaghi C, Bagga B, DeVincenzo JP, Cormier SA.
Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33.
PLoS Pathog. 2015;11:e1005217.
- Wu YH, Lai AC, Chi PY, Thio CL, Chen WY, Tsai CH, Lee YL, Lukacs NW,
Chang YJ. Pulmonary IL-33 orchestrates innate immune cells to mediate
respiratory syncytial virus-evoked airway hyperreactivity and
eosinophilia. Allergy. 2020;75:818-830.
- Lee SA, Kwak MS, Kim S, Shin JS. The role of high mobility group box 1
in innate immunity. Yonsei Med J. 2014;55:1165-76.
- Harris HE, Raucci A. Alarmin(g) news about danger: workshop on innate
danger signals and HMGB1. EMBO reports. 2006; 7:774–8.
- Chen S, Yu G, Xie J, Tang W, Gao L, Long X, Ren L, Xie X, Deng Y, Fu
Z, Liu E. High-mobility group box-1 protein from
CC10+ club cells promote type 2 response in the
later stage of respiratory syncytial virus infection. Am J Physiol
Lung Cell Mol Physiol. 2019;316:L280-L290.
- Manti S, Harford TJ, Salpietro C, Rezaee F, Piedimonte G. Induction of
high-mobility group Box-1 in vitro and in vivo by respiratory
syncytial virus. Pediatr Res. 2018;83:1049-1056.
- Loh Z, Simpson J, Ullah A, Zhang V, Gan WJ, Lynch JP, Werder RB,
Sikder AA, Lane K, Sim CB, Porrello E, Mazzone SB, Sly PD, Steptoe RJ,
Spann KM, Sukkar MB, Upham JW, Phipps S. HMGB1 amplifies ILC2-induced
type-2 inflammation and airway smooth muscle remodelling. PLoS Pathog.
2020;16:e1008651
- Hou C, Kong J, Liang Y, Huang H, Wen H, Zheng X, Wu L, Chen Y. HMGB1
contributes to allergen-induced airway remodeling in a murine model of
chronic asthma by modulating airway inflammation and activating lung
fibroblasts. Cell Mol Immunol. 2015;12:409-23.
- Ma L, Zeng J, Mo B, Wang C, Huang J, Sun Y, Yu Y, Liu S. High mobility
group box 1: a novel mediator of Th2-type response-induced airway
inflammation of acute allergic asthma. J Thorac Dis. 2015;7:1732-41.
- Xu M, Dong C. IL-25 in allergic inflammation. Immunol. Rev. 2017, 278,
185–191.
- Barlow JL, McKenzie AN. IL-25: a key requirement for the regulation of
type-2 immunity. BioFactors 2009, 35, 178–182.
- Yao X, Sun Y, Wang W, Sun Y. Interleukin (IL)-25: Pleiotropic roles in
asthma. Respirology 2016, 21, 638–647.
- Petersen BC, Dolgachev V, Rasky A, Lukacs NW. IL-17E (IL-25) and
IL-17RB promote respiratory syncytial virus-induced pulmonary disease.
J Leukoc Biol. 2014;95:809-815.
- Kaiko GE, Phipps S, Angkasekwinai P, Dong C, Foster PS. NK cell
deficiency predisposes to viral-induced Th2-type allergic inflammation
via epithelial-derived IL-25. J Immunol. 2010;185:4681-90.
- Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A, Morel PA,
Storkus WJ, Kalinski P. Dendritic cells mediate NK cell help for Th1
and CTL responses: two-signal requirement for the induction of NK cell
helper function. J Immunol. 2003;171:2366-73.
- Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki
A. Microbiota regulates immune defense against respiratory tract
influenza a virus infection. Proc Natl Acad Sci U S A.
2011;108:5354–9.
- Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg
GF, Paley MA, Antenus M, Williams KL, Erikson J, Wherry EJ, Artis D.
Commensal bacteria calibrate the activation threshold of innate
antiviral immunity. Immunity. 2012;37:158–70.
- Pu Q, Lin P, Gao P, Wang Z, Guo K, Qin S, Zhou C, Wang B, Wu E, Khan
N, Xia Z, Wei X, Wu M. Gut Microbiota Regulate Gut-Lung Axis
Inflammatory Responses by Mediating ILC2 Compartmental Migration. J
Immunol. 2021;207:257-267.
- Winkler C, Hochdorfer T, Israelsson E, Hasselberg A, Cavallin A, Thorn
K, et al. Activation of Group 2 Innate Lymphoid Cells After Allergen
Challenge in Asthmatic Patients. J Allergy Clin Immunol 2019;
144:61–9.e7.
- Constantinides MG. Interactions between the microbiota and innate and
innate-like lymphocytes. J Leukoc Biol. 2018;103:409-419.
- Britanova L, Diefenbach A. Interplay of innate lymphoid cells and the
microbiota. Immunol Rev. 2017;279:36-51.
- Maggi L, Montaini G, Mazzoni A, Rossettini B, Capone M, Rossi MC,
Santarlasci V, Liotta F, Rossi O, Gallo O, De Palma R, Maggi E, Cosmi
L, Romagnani S, Annunziato F. Human circulating group 2 innate
lymphoid cells can express CD154 and promote IgE production. J Allergy
Clin Immunol. 2017;139:964-976.e4.
- Hasegawa K, Linnemann RW, Mansbach JM, Ajami NJ, Espinola JA,
Petrosino JF, Piedra PA, Stevenson MD, Sullivan AF, Thompson AD,
Camargo CA Jr. The Fecal Microbiota Profile and Bronchiolitis in
Infants. Pediatrics. 2016;138:e20160218.
- Groves HT, Cuthbertson L, James P, Moffatt MF, Cox MJ, Tregoning JS.
Respiratory Disease following Viral Lung Infection Alters the Murine
Gut Microbiota. Front Immunol. 2018;9:182.
- Macfarlane S, Woodmansey EJ, Macfarlane GT. Colonization of mucin by
human intestinal bacteria and establishment of biofilm communities in
a two-stage continuous culture system. Appl Environ Microbiol
2005;71:7483–92.
- Wang J, Lu H, Yu L, Cheng W, Yan W, Jing X. Aggravation of airway
inflammation in RSV-infected asthmatic mice following
infection-induced alteration of gut microbiota. Ann Palliat Med.
2021;10:5084-5097.
- Li L, Wang F, Liu Y, Gu F. Intestinal microbiota dysbiosis in children
with recurrent respiratory tract infections. Microb Pathog.
2019;136:103709.
- Singh M, Ranjan Das R. Probiotics for allergic respiratory
diseases–putting it into perspective. Pediatr Allergy Immunol.
2010;21:e368-76
- Cardinale F, Lombardi E, Rossi O, Bagnasco D, Bellocchi A, Menzella F.
Epithelial dysfunction, respiratory infections and asthma: the
importance of immunomodulation. A focus on OM-85. Expert Rev Respir
Med. 2020;14:1019-1026.