Toll-like receptors ligand immunomodulators for the treatment congenital diaphragmatic hernia.
Congenital diaphragmatic hernia
Embryonic development
Fetal therapy
Inflammation
Macrophages
Orphan drug
Retinoic pathway
Toll-like receptors
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
18 Oct 2024
18 Oct 2024
Historique:
received:
02
07
2024
accepted:
23
09
2024
medline:
19
10
2024
pubmed:
19
10
2024
entrez:
18
10
2024
Statut:
epublish
Résumé
Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage. We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4 We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4 Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage.
METHODS
METHODS
We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4
RESULTS
RESULTS
We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4
CONCLUSIONS
CONCLUSIONS
Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.
Identifiants
pubmed: 39425191
doi: 10.1186/s13023-024-03384-7
pii: 10.1186/s13023-024-03384-7
doi:
Substances chimiques
Immunologic Factors
0
Toll-Like Receptors
0
Phenyl Ethers
0
Ligands
0
nitrofen
N71UYG034A
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
386Subventions
Organisme : Ministerio de Ciencia e Innovación
ID : SAF2016-75988-R
Organisme : Ministerio de Ciencia e Innovación
ID : PID2022-137487OB-I00
Organisme : Comunidad de Madrid
ID : S2017/BMD-3671. INFLAMUNE-CM
Organisme : Fundación MEHUER
ID : Ayuda Real e Ilustre Colegio Oficial de Farmaceuticos de Sevilla
Organisme : Fundación Ramón Areces
ID : Centro de Biología Molecular Severo Ochoa
Organisme : Fundación Banco Santander
ID : Centro d
Informations de copyright
© 2024. The Author(s).
Références
Leeuwen L, Fitzgerald DA. Congenital diaphragmatic hernia. J Paediatr Child Health. 2014;50(9):667–73.
pubmed: 24528549
doi: 10.1111/jpc.12508
Chatterjee D, Ing RJ, Gien J. Update on congenital diaphragmatic hernia. Anesth Analg. 2020;131(3):808–21.
pubmed: 31335403
doi: 10.1213/ANE.0000000000004324
Tovar JA. Congenital diaphragmatic hernia. Orphanet J Rare Dis. 2012;7:1.
pubmed: 22214468
pmcid: 3261088
doi: 10.1186/1750-1172-7-1
Greer JJ. Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. Respir Physiol Neurobiol. 2013;189(2):232–40.
pubmed: 23665522
doi: 10.1016/j.resp.2013.04.015
Kirby E, Keijzer R. Congenital diaphragmatic hernia: current management strategies from antenatal diagnosis to long-term follow-up. Pediatr Surg Int. 2020;36(4):415–29.
pubmed: 32072236
doi: 10.1007/s00383-020-04625-z
Deprest JA, Nicolaides K, Gratacos E. Fetal surgery for congenital diaphragmatic hernia is back from never gone. Fetal Diagn Ther. 2011;29(1):6–17.
pubmed: 21325858
doi: 10.1159/000322844
Coste K, Beurskens LW, Blanc P, Gallot D, Delabaere A, Blanchon L, et al. Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol. 2015;308(2):L147-157.
pubmed: 25416379
doi: 10.1152/ajplung.00108.2014
Greer JJ, Babiuk RP, Thebaud B. Etiology of congenital diaphragmatic hernia: the retinoid hypothesis. Pediatr Res. 2003;53(5):726–30.
pubmed: 12621107
doi: 10.1203/01.PDR.0000062660.12769.E6
Dalmer TRA, Clugston RD. Gene ontology enrichment analysis of congenital diaphragmatic hernia-associated genes. Pediatr Res. 2019;85(1):13–9.
pubmed: 30287891
doi: 10.1038/s41390-018-0192-8
Carmona R, Canete A, Cano E, Ariza L, Rojas A, Munoz-Chapuli R. Conditional deletion of WT1 in the septum transversum mesenchyme causes congenital diaphragmatic hernia in mice. eLife. 2016;5:69.
doi: 10.7554/eLife.16009
Iritani I. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol (Berl). 1984;169(2):133–9.
pubmed: 6742452
doi: 10.1007/BF00303142
Schreiner Y, Schaible T, Rafat N. Genetics of diaphragmatic hernia. Eur J Hum Genet. 2021;29(12):1729–33.
pubmed: 34621023
pmcid: 8632982
doi: 10.1038/s41431-021-00972-0
Yu L, Hernan RR, Wynn J, Chung WK. The influence of genetics in congenital diaphragmatic hernia. Semin Perinatol. 2020;44(1): 151169.
pubmed: 31443905
doi: 10.1053/j.semperi.2019.07.008
Nakamura H, Doi T, Puri P, Friedmacher F. Transgenic animal models of congenital diaphragmatic hernia: a comprehensive overview of candidate genes and signaling pathways. Pediatr Surg Int. 2020;36(9):991–7.
pubmed: 32591848
pmcid: 7385019
doi: 10.1007/s00383-020-04705-0
Clugston RD, Klattig J, Englert C, Clagett-Dame M, Martinovic J, Benachi A, et al. Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis. Am J Pathol. 2006;169(5):1541–9.
pubmed: 17071579
pmcid: 1780206
doi: 10.2353/ajpath.2006.060445
Kling DE, Schnitzer JJ. Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic hernia (CDH). Am J Med Genet C Semin Med Genet. 2007;145C(2):139–57.
pubmed: 17436305
doi: 10.1002/ajmg.c.30129
Noble BR, Babiuk RP, Clugston RD, Underhill TM, Sun H, Kawaguchi R, et al. Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen. Am J Physiol Lung Cell Mol Physiol. 2007;293(4):L1079-1087.
pubmed: 17704186
doi: 10.1152/ajplung.00286.2007
Nakazawa N, Takayasu H, Montedonico S, Puri P. Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung. Pediatr Surg Int. 2007;23(5):391–6.
pubmed: 17203325
doi: 10.1007/s00383-006-1848-8
Jones CV, Ricardo SD. Macrophages and CSF-1: implications for development and beyond. Organogenesis. 2013;9(4):249–60.
pubmed: 23974218
pmcid: 3903694
doi: 10.4161/org.25676
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2012;6:27.
Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9(4):259–70.
pubmed: 19282852
pmcid: 3648866
doi: 10.1038/nri2528
Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, Fleisch H, et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development. 1994;120(6):1357–72.
pubmed: 8050349
doi: 10.1242/dev.120.6.1357
Abood EA, Jones MM. Macrophages in developing mammalian skeletal muscle: evidence for muscle fibre death as a normal developmental event. Acta Anat. 1991;140(3):201–12.
pubmed: 1714222
doi: 10.1159/000147059
Correale J, Farez MF. Parasite infections in multiple sclerosis modulate immune responses through a retinoic acid-dependent pathway. J Immunol (Baltimore, Md: 1950). 2013;191(7):3827–37.
doi: 10.4049/jimmunol.1301110
Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL, Kasturi SP, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med. 2009;15(4):401–9.
pubmed: 19252500
pmcid: 2768543
doi: 10.1038/nm.1925
Perveen S, Ayasolla K, Zagloul N, Patel H, Ochani K, Orner D, et al. MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia. Pediatr Res. 2019;85(5):711–8.
pubmed: 30759452
doi: 10.1038/s41390-019-0335-6
Wang X, Zhou L. The multifaceted role of macrophages in homeostatic and injured skeletal muscle. Front Immunol. 2023;14:1274816.
pubmed: 37954602
pmcid: 10634307
doi: 10.3389/fimmu.2023.1274816
Abarca-Grau AM, Burbank LP, de Paz HD, Crespo-Rivas JC, Marco-Noales E, López MM, et al. Role for Rhizobium rhizogenes K84 cell envelope polysaccharides in surface interactions. Appl Environ Microbiol. 2012;78(6):1644–51.
pubmed: 22210213
pmcid: 3298171
doi: 10.1128/AEM.07117-11
Francisco S, Billod JM, Merino J, Punzon C, Gallego A, Arranz A, et al. Induction of TLR4/TLR2 interaction and heterodimer formation by low endotoxic atypical LPS. Front Immunol. 2021;12:748303.
pubmed: 35140704
doi: 10.3389/fimmu.2021.748303
Eiro N, Pidal I, Fernandez-Garcia B, Junquera S, Lamelas ML, del Casar JM, et al. Impact of CD68/(CD3+CD20) ratio at the invasive front of primary tumors on distant metastasis development in breast cancer. PLoS ONE. 2012;7(12):e52796.
pubmed: 23300781
pmcid: 3530508
doi: 10.1371/journal.pone.0052796
Askenazi SS, Perlman M. Pulmonary hypoplasia: lung weight and radial alveolar count as criteria of diagnosis. Arch Dis Child. 1979;54(8):614–8.
pubmed: 507916
pmcid: 1545796
doi: 10.1136/adc.54.8.614
Pries AR, Reglin B, Secomb TW. Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli. Hypertension. 2005;46(4):725–31.
pubmed: 16172421
doi: 10.1161/01.HYP.0000184428.16429.be
Guerrero NA, Camacho M, Vila L, Iniguez MA, Chillon-Marinas C, Cuervo H, et al. Cyclooxygenase-2 and prostaglandin E2 signaling through prostaglandin receptor EP-2 favor the development of myocarditis during acute trypanosoma cruzi infection. PLoS Negl Trop Dis. 2015;9(8):e0004025.
pubmed: 26305786
pmcid: 4549243
doi: 10.1371/journal.pntd.0004025
Cuervo H, Guerrero NA, Carbajosa S, Beschin A, De Baetselier P, Girones N, et al. Myeloid-derived suppressor cells infiltrate the heart in acute trypanosoma cruzi infection. J Immunol. 2011;187(5):2656–65.
pubmed: 21804013
doi: 10.4049/jimmunol.1002928
Kluth D, Kangah R, Reich P, Tenbrinck R, Tibboel D, Lambrecht W. Nitrofen-induced diaphragmatic hernias in rats: an animal model. J Pediatr Surg. 1990;25(8):850–4.
pubmed: 2401939
doi: 10.1016/0022-3468(90)90190-K
Baglaj SM, Czernik J. Nitrofen-induced congenital diaphragmatic hernia in rat embryo: what model? J Pediatr Surg. 2004;39(1):24–30.
pubmed: 14694366
doi: 10.1016/j.jpedsurg.2003.09.018
Wang YN, Tang Y, He Z, Ma H, Wang L, Liu Y, et al. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue. Nat Metab. 2021;3(11):1536–51.
pubmed: 34782792
doi: 10.1038/s42255-021-00482-9
Carlson RW, Forsberg LS, Kannenberg EL. Lipopolysaccharides in Rhizobium-legume symbioses. Subcell Biochem. 2010;53:339–86.
pubmed: 20593275
doi: 10.1007/978-90-481-9078-2_16
Matamoros-Recio A, Merino J, Gallego-Jiménez A, Conde-Alvarez R, Fresno M, Martín-Santamaría S. Immune evasion through Toll-like receptor 4: the role of the core oligosaccharides from α2-Proteobacteria atypical lipopolysaccharides. Carbohydr Polym. 2023;318:121094.
pubmed: 37479429
doi: 10.1016/j.carbpol.2023.121094
Lang RA, Bishop JM. Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell. 1993;74(3):453–62.
pubmed: 8348612
doi: 10.1016/0092-8674(93)80047-I
Martin P, D’Souza D, Martin J, Grose R, Cooper L, Maki R, et al. Wound healing in the PU.1 null mouse–tissue repair is not dependent on inflammatory cells. Curr Biol. 2003;13(13):1122–8.
pubmed: 12842011
doi: 10.1016/S0960-9822(03)00396-8
Jones CV, Williams TM, Walker KA, Dickinson H, Sakkal S, Rumballe BA, et al. M2 macrophage polarisation is associated with alveolar formation during postnatal lung development. Respir Res. 2013;14:41.
pubmed: 23560845
pmcid: 3626876
doi: 10.1186/1465-9921-14-41
Jalian HR, Liu PT, Kanchanapoomi M, Phan JN, Legaspi AJ, Kim J. All-trans retinoic acid shifts Propionibacterium acnes-induced matrix degradation expression profile toward matrix preservation in human monocytes. J Invest Dermatol. 2008;128(12):2777–82.
pubmed: 18563181
doi: 10.1038/jid.2008.155
Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce T(H)2 and tolerogenic responses. Nat Immunol. 2010;11(8):647–55.
pubmed: 20644570
doi: 10.1038/ni.1894
Holder AM, Klaassens M, Tibboel D, de Klein A, Lee B, Scott DA. Genetic factors in congenital diaphragmatic hernia. Am J Hum Genet. 2007;80(5):825–45.
pubmed: 17436238
pmcid: 1852742
doi: 10.1086/513442
Gilbert RM, Gleghorn JP. Connecting clinical, environmental, and genetic factors point to an essential role for vitamin A signaling in the pathogenesis of congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol. 2023;324(4):L456–67.
pubmed: 36749917
pmcid: 10042603
doi: 10.1152/ajplung.00349.2022
Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development (Cambridge, England). 1994;120(10):2749–71.
pubmed: 7607068
doi: 10.1242/dev.120.10.2749
Quadro L, Blaner WS, Salchow DJ, Vogel S, Piantedosi R, Gouras P, et al. Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J. 1999;18(17):4633–44.
pubmed: 10469643
pmcid: 1171537
doi: 10.1093/emboj/18.17.4633
Beurskens LW, Tibboel D, Lindemans J, Duvekot JJ, Cohen-Overbeek TE, Veenma DC, et al. Retinol status of newborn infants is associated with congenital diaphragmatic hernia. Pediatrics. 2010;126(4):712–20.
pubmed: 20837596
doi: 10.1542/peds.2010-0521
Clugston RD, Zhang W, Alvarez S, de Lera AR, Greer JJ. Understanding abnormal retinoid signaling as a causative mechanism in congenital diaphragmatic hernia. Am J Respir Cell Mol Biol. 2010;42(3):276–85.
pubmed: 19448158
doi: 10.1165/rcmb.2009-0076OC
Balounova J, Vavrochova T, Benesova M, Ballek O, Kolar M, Filipp D. Toll-like receptors expressed on embryonic macrophages couple inflammatory signals to iron metabolism during early ontogenesis. Eur J Immunol. 2014;44(5):1491–502.
pubmed: 24470066
doi: 10.1002/eji.201344040
Toelen J, Carlon M, Claus F, Gijsbers R, Sandaite I, Dierickx K, et al. The fetal respiratory system as target for antenatal therapy. Facts Views Vis Obgyn. 2011;3(1):22–35.
pubmed: 24753844
pmcid: 3991409