Surfactant Protein A Reduces TLR4 and Inflammatory Cytokine MRNA Levels in Neonatal Mouse Ileum

Overview

Journal Sci Rep

Specialty Science

Date 2021 Jan 29

PMID 33510368

Citations 5

Authors

Lidan Liu

Chaim Z Aron

Cullen M Grable

Adrian Robles

Xiangli Liu

Yuying Liu

Nicole Y Fatheree

J Marc Rhoads

Joseph L Alcorn

Affiliations

Soon will be listed here.

Abstract

Levels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A mice compared to wild type mice. Gavage of neonatal SP-A mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

Citing Articles

Chicken surfactant protein A1 activates macrophages phagocytosis and attenuates LPS-induced inflammatory response through the TLR4-mediated NF-кB pathway.

Zhou Q, Xiong H, Wu H, Wang C, Chen X, Liu H Poult Sci. 2025; 104(3):104854.

PMID: 39879901 PMC: 11815655. DOI: 10.1016/j.psj.2025.104854.

Impact of vitamin D on hyperoxic acute lung injury in neonatal mice.

Tran T, Davies J, Johnston R, Karmouty-Quintana H, Li H, Crocker C BMC Pulm Med. 2024; 24(1):584.

PMID: 39587520 PMC: 11587781. DOI: 10.1186/s12890-024-03391-1.

Surfactant protein a attenuates generalized and localized neuroinflammation in neonatal mice.

Crocker C, Sharmeen R, Tran T, Khan A, Li W, Alcorn J Brain Res. 2023; 1807:148308.

PMID: 36871846 PMC: 10065943. DOI: 10.1016/j.brainres.2023.148308.

Innate and Adaptive Immunity during SARS-CoV-2 Infection: Biomolecular Cellular Markers and Mechanisms.

Brown B, Ojha V, Fricke I, Al-Sheboul S, Imarogbe C, Gravier T Vaccines (Basel). 2023; 11(2).

PMID: 36851285 PMC: 9962967. DOI: 10.3390/vaccines11020408.

Necrotizing enterocolitis in premature infants-A defect in the brakes? Evidence from clinical and animal studies.

Sampath V, Martinez M, Caplan M, Underwood M, Cuna A Mucosal Immunol. 2023; 16(2):208-220.

PMID: 36804483 PMC: 10243706. DOI: 10.1016/j.mucimm.2023.02.002.

References

Wright J . Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005; 5(1):58-68. DOI: 10.1038/nri1528. View

Afrazi A, Sodhi C, Richardson W, Neal M, Good M, Siggers R . New insights into the pathogenesis and treatment of necrotizing enterocolitis: Toll-like receptors and beyond. Pediatr Res. 2010; 69(3):183-8. PMC: 3125129. DOI: 10.1203/PDR.0b013e3182093280. View

Wu Y, Adam S, Hamann L, Heine H, Ulmer A, Buwitt-Beckmann U . Accumulation of inhibitory kappaB-alpha as a mechanism contributing to the anti-inflammatory effects of surfactant protein-A. Am J Respir Cell Mol Biol. 2004; 31(6):587-94. DOI: 10.1165/rcmb.2004-0003OC. View

Caplan M, Simon D, Jilling T . The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis. Semin Pediatr Surg. 2005; 14(3):145-51. DOI: 10.1053/j.sempedsurg.2005.05.002. View

Good M, Siggers R, Sodhi C, Afrazi A, Alkhudari F, Egan C . Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci U S A. 2012; 109(28):11330-5. PMC: 3396489. DOI: 10.1073/pnas.1200856109. View

Fukata M, Abreu M . TLR4 signalling in the intestine in health and disease. Biochem Soc Trans. 2007; 35(Pt 6):1473-8. DOI: 10.1042/BST0351473. View

Khailova L, Dvorak K, Arganbright K, Halpern M, Kinouchi T, Yajima M . Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2010; 297(5):G940-9. PMC: 2777452. DOI: 10.1152/ajpgi.00141.2009. View

Hubbard L, Moore B . IRAK-M regulation and function in host defense and immune homeostasis. Infect Dis Rep. 2011; 2(1). PMC: 3049547. DOI: 10.4081/idr.2010.e9. View

Neu J, Walker W . Necrotizing enterocolitis. N Engl J Med. 2011; 364(3):255-64. PMC: 3628622. DOI: 10.1056/NEJMra1005408. View

10.

Stamme C, Muller M, Hamann L, Gutsmann T, Seydel U . Surfactant protein a inhibits lipopolysaccharide-induced immune cell activation by preventing the interaction of lipopolysaccharide with lipopolysaccharide-binding protein. Am J Respir Cell Mol Biol. 2002; 27(3):353-60. DOI: 10.1165/rcmb.4812. View

11.

Neal M, Jia H, Eyer B, Good M, Guerriero C, Sodhi C . Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors. PLoS One. 2013; 8(6):e65779. PMC: 3680486. DOI: 10.1371/journal.pone.0065779. View

12.

Sorensen G, Husby S, Holmskov U . Surfactant protein A and surfactant protein D variation in pulmonary disease. Immunobiology. 2007; 212(4-5):381-416. DOI: 10.1016/j.imbio.2007.01.003. View

13.

Awasthi S, Madhusoodhanan R, Wolf R . Surfactant protein-A and toll-like receptor-4 modulate immune functions of preterm baboon lung dendritic cell precursor cells. Cell Immunol. 2011; 268(2):87-96. PMC: 3104394. DOI: 10.1016/j.cellimm.2011.02.009. View

14.

Kishore U, Greenhough T, Waters P, Shrive A, Ghai R, Kamran M . Surfactant proteins SP-A and SP-D: structure, function and receptors. Mol Immunol. 2005; 43(9):1293-315. DOI: 10.1016/j.molimm.2005.08.004. View

15.

Liu Y, Zhu L, Fatheree N, Liu X, Pacheco S, Tatevian N . Changes in intestinal Toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2009; 297(3):G442-50. PMC: 2739826. DOI: 10.1152/ajpgi.00182.2009. View

16.

Rakhesh M, Cate M, Vijay R, Shrikant A, Shanjana A . A TLR4-interacting peptide inhibits lipopolysaccharide-stimulated inflammatory responses, migration and invasion of colon cancer SW480 cells. Oncoimmunology. 2012; 1(9):1495-1506. PMC: 3525605. DOI: 10.4161/onci.22089. View

17.

Levine A, Whitsett J . Pulmonary collectins and innate host defense of the lung. Microbes Infect. 2001; 3(2):161-6. DOI: 10.1016/s1286-4579(00)01363-0. View

18.

Le Huerou-Luron I, Blat S, Boudry G . Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects. Nutr Res Rev. 2010; 23(1):23-36. DOI: 10.1017/S0954422410000065. View

19.

Gribar S, Sodhi C, Richardson W, Anand R, Gittes G, Branca M . Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis. J Immunol. 2008; 182(1):636-46. PMC: 3761063. DOI: 10.4049/jimmunol.182.1.636. View

20.

Grave G, Nelson S, Walker W, Moss R, Dvorak B, Hamilton F . New therapies and preventive approaches for necrotizing enterocolitis: report of a research planning workshop. Pediatr Res. 2007; 62(4):510-4. DOI: 10.1203/PDR.0b013e318142580a. View