Dysregulation of Immunity in Pulmonary Fibrosis is Associated with Increased Myeloid-specific Triggering Receptor-1 and Transforming Growth Factor-beta1 Expression
Abstract
Fibrosing pneumonia (FP) is classified into usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), each having its own etiology and prognosis. Both types of FP are progressive and chronic conditions with distinct etiologies. Cytokines and inflammatory mediators play critical roles in the pathogenesis of FP. Among them, the role of transforming growth factor beta-1 (TGF-β1) and modulators triggering fibrosis are not well understood. In this study, the expression of triggering receptor expressed on myeloid cells-1 (TREM-1) as a stimulator for the production of TGF-β1 and also CD4+CD25+Foxp3+ regulatory cells were investigted in FP patients.
Sixteen UIP, 14 NSIP and 4 pulmonary fibrosis following Mycobacterium tuberculosis (TB) infection patients, were compared with 12 healthy controls. The frequency of blood CD14+TGF-β1+ and CD14+TREM1+-gated monocytes and CD4+CD25+Foxp3+ regulatory T cells (Treg), as well as the plasma levels of TGF-β1 and IL‑10 were measured.
Fibrosis patients compared to healthy controls had a greater frequency of CD14+TGF-β1+ [15.9 (0.2-88.2) vs. 0.6 (0.2-11.0)] and CD14+TREM1+ [21.1 (2.3-91.2) vs. 10.3 (3.1-28.6)]-gated monocytes, and CD4+CD25+Foxp3+ [1.2 (0.3-3.6) vs. 0.2 (0.1-0.4)]-gated lymphocytes. Plasma TGF-β1 were also significantly increased in patients with fibrosis compared to healthy controls [9316.2 (±5554.4) vs. 3787.5 (±2255.6)].
These results confirm the importance of TGF-β1 and TREM1 in pulmonary fibrosis. It seems that this reciprocal cycle in healthy people is modulated by the production of IL‑10 by Treg cells, thus limiting fibrosis, as observed in patients following TB infection. Further investigations are recommended to evaluate possible immunomodulatory mechanisms defects in pulmonary fibrosis.
1. Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology and regulation. 2009 Mar. Mucosal Immunol;2(2):103-21.
2. Roe K, Gibot S, Verma S. Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? 2014. Front Microbiol;5:627.
3. Tammaro A, Derive M, Gibot S, Leemans JC, Florquin S, Dessing MC. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives. 2017 Sep. Pharmacol Ther;177:81-95.
4. Colonna M, Facchetti F. TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. 2003 Jun 15. J Infect Dis;187 Suppl 2:S397-401.
5. Kuemmel A, Alflen A, Schmidt LH, Sebastian M, Wiewrodt R, Schulze AB, Buhl R, Radsak M. Soluble Triggering Receptor Expressed on Myeloid Cells 1 in lung cancer. 2018 Jul 17. Sci Rep;8(1):10766.
6. Tomita H, Ogawa F, Hara T, Yanaba K, Iwata Y, Muroi E, Yoshizaki A, Komura K, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, Sato S. Elevated serum concentrations of triggering receptor expressed on myeloid cells-1 in diffuse cutaneous systemic sclerosis: association with severity of pulmonary fibrosis. 2010 Apr. J Rheumatol;37(4):787-91.
7. Wells AU. Managing diagnostic procedures in idiopathic pulmonary fibrosis. 2013 Jun 1. Eur Respir Rev;22(128):158-62.
8. Travis WD, Hunninghake G, King TE, Jr., Lynch DA, Colby TV, Galvin JR, Brown KK, Chung MP, Cordier JF, du Bois RM, Flaherty KR, Franks TJ, Hansell DM, Hartman TE, Kazerooni EA, Kim DS, Kitaichi M, Koyama T, Martinez FJ, Nagai S, Midthun DE, Müller NL, Nicholson AG, Raghu G, Selman M, Wells A. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. 2008 Jun 15. Am J Respir Crit Care Med;177(12):1338-47.
9. Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. 2008 Mar 26. Orphanet J Rare Dis;3:8.
10. Peng L, Zhou Y, Dong L, Chen RQ, Sun GY, Liu T, Ran WZ, Fang X, Jiang JX, Guan CX. TGF-beta1 Upregulates the Expression of Triggering Receptor Expressed on Myeloid Cells 1 in Murine Lungs. 2016 Jan 7. Sci Rep;6:18946.
11. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE, Jr., Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. 2011 Mar 15. Am J Respir Crit Care Med;183(6):788-824.
12. Brown AW, Nathan SD. The Value and Application of the 6-Minute-Walk Test in Idiopathic Pulmonary Fibrosis. 2018 Jan. Ann Am Thorac Soc;15(1):3-10.
13. Kolb M, Collard HR. Staging of idiopathic pulmonary fibrosis: past, present and future. 2014 Jun. Eur Respir Rev;23(132):220-4.
14. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). 2000 Feb. Am J Respir Crit Care Med;161(2 Pt 1):646-64.
15. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. 2006 Oct 1. Am J Respir Crit Care Med;174(7):810-6.
16. Fell CD, Martinez FJ, Liu LX, Murray S, Han MK, Kazerooni EA, Gross BH, Myers J, Travis WD, Colby TV, Toews GB, Flaherty KR. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. 2010 Apr 15. Am J Respir Crit Care Med;181(8):832-7.
17. du Bois R, King TE, Jr. Challenges in pulmonary fibrosis x 5: the NSIP/UIP debate. 2007 Nov. Thorax;62(11):1008-12.
18. Nathan SD, Brown AW, Mogulkoc N, Soares F, Collins AC, Cheng J, Peterson J, Cannon B, King CS, Barnett SD. The association between white blood cell count and outcomes in patients with idiopathic pulmonary fibrosis. 2020 Aug-Sep. Respir Med;170:106068.
19. Achaiah A, Rathnapala A, Pereira A, Bothwell H, Dwivedi K, Barker R, Iotchkova V, Benamore R, Hoyles RK, Ho LP. Neutrophil lymphocyte ratio as an indicator for disease progression in Idiopathic Pulmonary Fibrosis. 2022 Jun. BMJ Open Respir Res;9(1).
20. Dantas P, Matos AO, da Silva Filho E, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. 2020. Int Rev Immunol;39(4):188-202.
21. Suchankova M, Urban J, Ganovska M, Tibenska E, Szaboova K, Tedlova E, Sandor F, Majer I, Bobovcak M, Jonner I, Konig B, Bucova M. TREM-1 and TREM-2 Expression on CD14(+) Cells in Bronchoalveolar Lavage Fluid in Pulmonary Sarcoidosis and Hypersensitivity Pneumonitis in the Context of T Cell Immune Response. 2020. Mediators Inflamm;2020:9501617.
22. Nguyen-Lefebvre AT, Ajith A, Portik-Dobos V, Horuzsko DD, Arbab AS, Dzutsev A, Sadek R, Trinchieri G, Horuzsko A. The innate immune receptor TREM-1 promotes liver injury and fibrosis. 2018 Nov 1. J Clin Invest;128(11):4870-83.
23. Dower K, Ellis DK, Saraf K, Jelinsky SA, Lin LL. Innate immune responses to TREM-1 activation: overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide. 2008 Mar 1. J Immunol;180(5):3520-34.
24. Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, Shevach EM. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. 2008 Sep 1. J Exp Med;205(9):1975-81.
25. King TE, Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. 2011 Dec 3. Lancet;378(9807):1949-61.
26. Reilkoff RA, Peng H, Murray LA, Peng X, Russell T, Montgomery R, Feghali-Bostwick C, Shaw A, Homer RJ, Gulati M, Mathur A, Elias JA, Herzog EL. Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis. 2013 Jan 15. Am J Respir Crit Care Med;187(2):180-8.
27. Moore BB, Fry C, Zhou Y, Murray S, Han MK, Martinez FJ, Flaherty KR. Inflammatory leukocyte phenotypes correlate with disease progression in idiopathic pulmonary fibrosis. 2014 Dec 22. Front Med;1(56).
28. Shimizu Y, Dobashi K, Endou K, Ono A, Yanagitani N, Utsugi M, Sano T, Ishizuka T, Shimizu K, Tanaka S, Mori M. Decreased interstitial FOXP3(+) lymphocytes in usual interstitial pneumonia with discrepancy of CXCL12/CXCR4 axis. 2010 Apr-Jun. Int J Immunopathol Pharmacol;23(2):449-61.
29. Kotsianidis I, Nakou E, Bouchliou I, Tzouvelekis A, Spanoudakis E, Steiropoulos P, Sotiriou I, Aidinis V, Margaritis D, Tsatalas C, Bouros D. Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis. 2009 Jun 15. Am J Respir Crit Care Med;179(12):1121-30.
30. Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. 2003 Oct 20. J Exp Med;198(8):1179-88.
2. Roe K, Gibot S, Verma S. Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? 2014. Front Microbiol;5:627.
3. Tammaro A, Derive M, Gibot S, Leemans JC, Florquin S, Dessing MC. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives. 2017 Sep. Pharmacol Ther;177:81-95.
4. Colonna M, Facchetti F. TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. 2003 Jun 15. J Infect Dis;187 Suppl 2:S397-401.
5. Kuemmel A, Alflen A, Schmidt LH, Sebastian M, Wiewrodt R, Schulze AB, Buhl R, Radsak M. Soluble Triggering Receptor Expressed on Myeloid Cells 1 in lung cancer. 2018 Jul 17. Sci Rep;8(1):10766.
6. Tomita H, Ogawa F, Hara T, Yanaba K, Iwata Y, Muroi E, Yoshizaki A, Komura K, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, Sato S. Elevated serum concentrations of triggering receptor expressed on myeloid cells-1 in diffuse cutaneous systemic sclerosis: association with severity of pulmonary fibrosis. 2010 Apr. J Rheumatol;37(4):787-91.
7. Wells AU. Managing diagnostic procedures in idiopathic pulmonary fibrosis. 2013 Jun 1. Eur Respir Rev;22(128):158-62.
8. Travis WD, Hunninghake G, King TE, Jr., Lynch DA, Colby TV, Galvin JR, Brown KK, Chung MP, Cordier JF, du Bois RM, Flaherty KR, Franks TJ, Hansell DM, Hartman TE, Kazerooni EA, Kim DS, Kitaichi M, Koyama T, Martinez FJ, Nagai S, Midthun DE, Müller NL, Nicholson AG, Raghu G, Selman M, Wells A. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. 2008 Jun 15. Am J Respir Crit Care Med;177(12):1338-47.
9. Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. 2008 Mar 26. Orphanet J Rare Dis;3:8.
10. Peng L, Zhou Y, Dong L, Chen RQ, Sun GY, Liu T, Ran WZ, Fang X, Jiang JX, Guan CX. TGF-beta1 Upregulates the Expression of Triggering Receptor Expressed on Myeloid Cells 1 in Murine Lungs. 2016 Jan 7. Sci Rep;6:18946.
11. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE, Jr., Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. 2011 Mar 15. Am J Respir Crit Care Med;183(6):788-824.
12. Brown AW, Nathan SD. The Value and Application of the 6-Minute-Walk Test in Idiopathic Pulmonary Fibrosis. 2018 Jan. Ann Am Thorac Soc;15(1):3-10.
13. Kolb M, Collard HR. Staging of idiopathic pulmonary fibrosis: past, present and future. 2014 Jun. Eur Respir Rev;23(132):220-4.
14. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). 2000 Feb. Am J Respir Crit Care Med;161(2 Pt 1):646-64.
15. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. 2006 Oct 1. Am J Respir Crit Care Med;174(7):810-6.
16. Fell CD, Martinez FJ, Liu LX, Murray S, Han MK, Kazerooni EA, Gross BH, Myers J, Travis WD, Colby TV, Toews GB, Flaherty KR. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. 2010 Apr 15. Am J Respir Crit Care Med;181(8):832-7.
17. du Bois R, King TE, Jr. Challenges in pulmonary fibrosis x 5: the NSIP/UIP debate. 2007 Nov. Thorax;62(11):1008-12.
18. Nathan SD, Brown AW, Mogulkoc N, Soares F, Collins AC, Cheng J, Peterson J, Cannon B, King CS, Barnett SD. The association between white blood cell count and outcomes in patients with idiopathic pulmonary fibrosis. 2020 Aug-Sep. Respir Med;170:106068.
19. Achaiah A, Rathnapala A, Pereira A, Bothwell H, Dwivedi K, Barker R, Iotchkova V, Benamore R, Hoyles RK, Ho LP. Neutrophil lymphocyte ratio as an indicator for disease progression in Idiopathic Pulmonary Fibrosis. 2022 Jun. BMJ Open Respir Res;9(1).
20. Dantas P, Matos AO, da Silva Filho E, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. 2020. Int Rev Immunol;39(4):188-202.
21. Suchankova M, Urban J, Ganovska M, Tibenska E, Szaboova K, Tedlova E, Sandor F, Majer I, Bobovcak M, Jonner I, Konig B, Bucova M. TREM-1 and TREM-2 Expression on CD14(+) Cells in Bronchoalveolar Lavage Fluid in Pulmonary Sarcoidosis and Hypersensitivity Pneumonitis in the Context of T Cell Immune Response. 2020. Mediators Inflamm;2020:9501617.
22. Nguyen-Lefebvre AT, Ajith A, Portik-Dobos V, Horuzsko DD, Arbab AS, Dzutsev A, Sadek R, Trinchieri G, Horuzsko A. The innate immune receptor TREM-1 promotes liver injury and fibrosis. 2018 Nov 1. J Clin Invest;128(11):4870-83.
23. Dower K, Ellis DK, Saraf K, Jelinsky SA, Lin LL. Innate immune responses to TREM-1 activation: overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide. 2008 Mar 1. J Immunol;180(5):3520-34.
24. Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, Shevach EM. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. 2008 Sep 1. J Exp Med;205(9):1975-81.
25. King TE, Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. 2011 Dec 3. Lancet;378(9807):1949-61.
26. Reilkoff RA, Peng H, Murray LA, Peng X, Russell T, Montgomery R, Feghali-Bostwick C, Shaw A, Homer RJ, Gulati M, Mathur A, Elias JA, Herzog EL. Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis. 2013 Jan 15. Am J Respir Crit Care Med;187(2):180-8.
27. Moore BB, Fry C, Zhou Y, Murray S, Han MK, Martinez FJ, Flaherty KR. Inflammatory leukocyte phenotypes correlate with disease progression in idiopathic pulmonary fibrosis. 2014 Dec 22. Front Med;1(56).
28. Shimizu Y, Dobashi K, Endou K, Ono A, Yanagitani N, Utsugi M, Sano T, Ishizuka T, Shimizu K, Tanaka S, Mori M. Decreased interstitial FOXP3(+) lymphocytes in usual interstitial pneumonia with discrepancy of CXCL12/CXCR4 axis. 2010 Apr-Jun. Int J Immunopathol Pharmacol;23(2):449-61.
29. Kotsianidis I, Nakou E, Bouchliou I, Tzouvelekis A, Spanoudakis E, Steiropoulos P, Sotiriou I, Aidinis V, Margaritis D, Tsatalas C, Bouros D. Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis. 2009 Jun 15. Am J Respir Crit Care Med;179(12):1121-30.
30. Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. 2003 Oct 20. J Exp Med;198(8):1179-88.
| Files | ||
| Issue | Vol 22 No 1 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i1.12002 | |
| Keywords | ||
| Interleukin-10 Idiopathic pulmonary fibrosis Flow cytometry Triggering receptor expressed on myeloid cells-1 Transforming growth factor beta T-lymphocytes Regulatory | ||
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How to Cite
1.
Rasouli S, Heshmatnia J, Mosaffa N, Marjani M, Mortaz E. Dysregulation of Immunity in Pulmonary Fibrosis is Associated with Increased Myeloid-specific Triggering Receptor-1 and Transforming Growth Factor-beta1 Expression. Iran J Allergy Asthma Immunol. 2023;22(1):12-24.
