Comparative characteristics of TRP channels expression levels on the macrophages of patients with chronic obstructive pulmonary disease

Introduction. Macrophages are one of the key cells in the pathogenesis of chronic obstructive pulmonary disease (COPD), mediating the primary immune response and coordinating the further reaction of the immune system upon contact with cigarette smoke and air pollutants. It is known that some TRP channels expressed on macrophages are receptors for dust particles and cigarette smoke components.
Aim. To study the features of TRPV1, TRPV4, TRPA1 and TRPM8 channels expression on monocyte-derived macrophages and alveolar macrophages of COPD patients and smokers without bronchial obstruction.
Materials and methods. Expression of TRP channels at the mRNA level was studied in monocyte-derived macrophages obtained from 8 COPD patients and 6 healthy smokers by quantitative reverse transcription PCR. Expression of TRP channels at the protein level was studied on alveolar macrophages of 39 COPD patients and 8 healthy smokers by indirect flow cytometry.
Results. It was found that under in vitro conditions, monocyte-derive macrophages of COPD patients were distinguished by a significant 4.8-fold increase in the number of TRPV1 transcripts (p=0.009). At the same time, the expression of the TRPV1 protein on the alveolar macrophages of COPD patients was also significantly higher when compared to the cells of smokers from the control group (14.1 [6.4‒21.2]% vs. 6.1 [2.1‒9.8]%, p=0.006). In addition, we found that TRPV4 expression was increased among active smokers with COPD, and the expression of TRPA1 and TRPM8 channels correlated with some lung function parameters.
Conclusion. The obtained results suggest that the increased expression of TRPV1 on macrophages may be a marker of the disease and contribute to its development, while the expression of TRPV4, TRPA1 and TRPM8 may influence the clinical course of COPD.

1. Adeloye D., Song P., Zhu Y., Campbell H., Sheikh A., Rudan I.; NIHR RESPIRE Global Respiratory Health Unit. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med. 2022; 10(5):447–458. https://doi.org/10.1016/S2213-2600(21)00511-7

2. Zou J., Sun T., Song X., Liu Y.M., Lei F., Chen M.M., Chen Z., Zhang P., Ji Y.X., Zhang X.J., She Z.G., Cai J., Luo Y., Wang P., Li H. Distributions and trends of the global burden of COPD attributable to risk factors by SDI, age, and sex from 1990 to 2019: a systematic analysis of GBD 2019 data. Respir. Res. 2022; 23(1):90. https://doi.org/10.1186/s12931-022-02011-y

3. Safiri S., Carson-Chahhoud K., Noori M., Nejadghaderi S.A., Sullman M.J.M., Ahmadian Heris J., Ansarin K., Mansournia M.A., Collins G.S., Kolahi A.A., Kaufman J.S. Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019. BMJ 2022; 378:e069679. https://doi.org/10.1136/bmj-2021-069679

4. Kotlyarov S. Involvement of the Innate Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Int. J. Mol. Sci. 2022. 23(2):985. https://doi.org/10.3390/ijms23020985

5. Finicelli M., Digilio F.A., Galderisi U., Peluso G. The Emerging Role of Macrophages in Chronic Obstructive Pulmonary Disease: The Potential Impact of Oxidative Stress and Extracellular Vesicle on Macrophage Polarization and Function. Antioxidants (Basel) 2022; 11(3):464. https://doi.org/10.3390/antiox11030464

6. Milici A, Talavera K. TRP Channels as Cellular Targets of Particulate Matter. Int. J. Mol. Sci. 2021; 22(5):2783. https://doi.org/10.3390/ijms22052783

7. Baxter M., Eltom S., Dekkak B., Yew-Booth L., Dubuis E.D., Maher S.A., Belvisi M.G., Birrell M.A. Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax 2014; 69(12):1080–1089. https://doi.org/10.1136/thoraxjnl-2014-205467

8. Li M., Li Q., Yang G., Kolosov V.P., Perelman J.M., Zhou X.D. Cold temperature induces mucin hypersecretion from normal human bronchial epithelial cells in vitro through a transient receptor potential melastatin 8 (TRPM8)-mediated mechanism. J. Allergy Clin. Immunol. 2011; 128(3):626‒634.e1-5. https://doi.org/10.1016/j.jaci.2011.04.032

9. Xiong M., Guo M., Huang D., Li J., Zhou Y. TRPV1 genetic polymorphisms and risk of COPD or COPD combined with PH in the Han Chinese population. Cell Cycle 2020; 19(22):3066–3073. https://doi.org/10.1080/15384101.2020.1831246

10. Wang M., Zhang Y., Xu M., Zhang H., Chen Y., Chung K.F., Adcock I.M., Li F. Roles of TRPA1 and TRPV1 in cigarette smoke -induced airway epithelial cell injury model. Free Radic. Biol. Med. 2019; 134:229–238. https://doi.org/10.1016/j.freeradbiomed.2019.01.004

11. Jian T., Chen J., Ding X., Lv H., Li J., Wu Y., Ren B., Tong B., Zuo Y., Su K., Li W. Flavonoids isolated from loquat (Eriobotrya japonica) leaves inhibit oxidative stress and inflammation induced by cigarette smoke in COPD mice: the role of TRPV1 signaling pathways. Food Funct. 2020; 11(4):3516–3526. https://doi.org/10.1039/c9fo02921d

12. Birrell M.A., Bonvini S.J., Dubuis E., Maher S.A., Wortley M.A., Grace M.S., Raemdonck K., Adcock J.J., Belvisi M.G. Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect? J. Allergy Clin. Immunol. 2014; 133(3):679–687.e9. https://doi.org/10.1016/j.jaci.2013.12.003

13. Lv Z., Xu X., Sun Z., Yang Y.X., Guo H., Li J., Sun K., Wu R., Xu J., Jiang Q., Ikegawa S., Shi D. TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via Ca2+/CaMKII/Nrf2 signaling pathway. Cell Death Dis. 2021; 12(6):504. https://doi.org/10.1038/s41419-021-03792-8

14. Zhao J.F., Ching L.C., Kou Y.R., Lin S.J., Wei J., Shyue S.K., Lee T.S. Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages: role of liver X receptor α. Mediators Inflamm. 2013; 2013:925171. https://doi.org/10.1155/2013/925171

15. Ninomiya Y., Tanuma S.I., Tsukimoto M. Differences in the effects of four TRPV1 channel antagonists on lipopolysaccharide- induced cytokine production and COX-2 expression in murine macrophages. Biochem. Biophys. Res. Commun. 2017; 484(3):668–674. https://doi.org/10.1016/j.bbrc.2017.01.173

16. Jiang X., Wang C., Ke Z., Duo L., Wu T., Wang W., Yang Y., Dai Y. The ion channel TRPV1 gain-of-function reprograms the immune microenvironment to facilitate colorectal tumorigenesis. Cancer Lett. 2022; 527:95–106. https://doi.org/10.1016/j.canlet.2021.12.012

17. Fernandes E.S., Liang L., Smillie S.J., Kaiser F., Purcell R., Rivett D.W., Alam S., Howat S., Collins H., Thompson S.J., Keeble J.E., Riffo-Vasquez Y., Bruce K.D., Brain S.D. TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome. J. Immunol. 2012; 188(11):5741–5751. https://doi.org/10.4049/jimmunol.1102147

18. Kim C.S., Kawada T., Kim B.S., Han I.S., Choe S.Y., Kurata T., Yu R. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell Signal. 2003; 15(3):299‒306. https://doi.org/10.1016/s0898-6568(02)00086-4

19. Rao Y., Gai X., Xiong J., Le Y., Sun Y. Transient Receptor Potential Cation Channel Subfamily V Member 4 Mediates Pyroptosis in Chronic Obstructive Pulmonary Disease. Front. Physiol. 2021; 12:783891. https://doi.org/10.3389/fphys.2021.783891

20. Nguyen T.N., Siddiqui G., Veldhuis N.A., Poole D.P. Diverse Roles of TRPV4 in Macrophages: A Need for Unbiased Profiling. Front. Immunol. 2022; 12:828115. https://doi.org/10.3389/fimmu.2021.828115

21. Hornsby E., King H.W., Peiris M., Buccafusca R., Lee W.J., Wing E.S., Blackshaw L.A., Lindsay J.O., Stagg A.J. The cation channel TRPM8 influences the differentiation and function of human monocytes. J. Leukoc. Biol. 2022; 112(3):365–381. https://doi.org/10.1002/JLB.1HI0421-181R

22. Naert R., López-Requena A., Talavera K. TRPA1 Expression and Pathophysiology in Immune Cells. Int. J. Mol. Sci. 2021; 22(21):11460. https://doi.org/10.3390/ijms222111460