- Research Letter
- Open Access
Interleukin-34: an important modifier in the pathogenesis of influenza pneumonia
Critical Care volume 25, Article number: 274 (2021)
Influenza is an acute respiratory virus infection of worldwide health importance [1, 2]. Interleukin-34 (IL-34) is an important inflammatory cytokine [3, 4]. We tested here whether IL-34 contributes to the immunopathology of influenza virus infection.
Twenty-two H1N1-infected patients were enrolled, and seven H1N1 patients were diagnosed with severe pneumonia. There was a dramatic increase in serum IL-34 levels in H1N1 patients at initial diagnosis (Fig. 1a). Influenza patients with severe disease displayed significantly higher serum IL-34 levels compared with those with mild disease (Fig. 1b). Besides, serum IL-34 concentrations were significantly decreased after these patients had recovered from acute infection (Fig. 1c). Furthermore, female C57BL/6Je mice (8–10 weeks of age) were intranasally infected with 20 TCID50 of influenza virus strain A/PR/8/34 (H1N1), and we found that IL-34 levels were significantly increased in the lung and blood after H1N1 infection (Fig. 1d).
Next, a lethal murine model was established by intranasally infecting female C57BL/6Je mice with 90 tissue culture infectious dose 50 (TCID50) of influenza virus strain A/PR/8/34, and body weight and survival change was assessed out to 14 day. IL-34 blockade was performed by tail vein injection with 10 μg of sheep anti-mouse IL-34 antibody (R&D systems, AF5195) on day of influenza infection, followed by booster doses of 5 μg on day 2 and 4. We found that mice treated with anti-IL-34 antibodies suffered significantly less weight loss than mice treated with IgG control and started to regain body weight by day 8 after viral infection, while mice treated with IgG control continued to lose body weight until death (Fig. 1e). Furthermore, all of mice treated with IgG control were dead within 11 days post infection, whereas 50% of mice treated with anti-IL-34 antibodies survived beyond day 14 post infection (Fig. 1f). Virus titers were also measured from lung tissues 5 days post infection. Interestingly, viral titers were similar between IgG control and anti-IL-34-treated mice (Fig. 1g), suggesting that IL-34 up-regulation did not affect influenza virus replication in the lung. We assessed the histological changes of lung injury using a standardized lung injury scoring system , and the lung injury score was significantly lower in mice treated with anti-IL-34 antibodies as compared to mice treated with IgG control (Fig. 1h).
We further investigated the direct influence of IL-34 on non-lethal influenza virus infection, C57BL/6Je mice were intranasally infected with influenza virus strain PR8 at a dose of 20 TCID50 and then 2 μg of recombinant mouse IL-34 protein (R&D systems, 5195-ML) was inoculated into mice through tail vein injection. In mice treated with recombinant IL-34 protein, we observed a more severe decrease in weight following infection and a delayed recovery compared to mice treated with saline control (Fig. 1i). Moreover, all of mice treated with saline control survived beyond day 14 post non-lethal influenza virus infection, whereas 40% mice treated with recombinant IL-34 protein were dead within 5 days post infection (Fig. 1j). We next examined viral clearance by quantitating lung viral titers in mice treated with or without IL-34 on day 5 after non-lethal influenza virus infection, and there was no significant difference in viral titers (Fig. 1k). Histological evaluation revealed that the lung injury score was significantly higher in IL-34-treated mice as compared to saline-treated mice after non-lethal influenza virus infection (Fig. 1l).
Collectively, our data demonstrated a detrimental role of IL-34 in the immunopathology of influenza virus infection. We therefore speculate that excessive IL-34 amounts may have important implications in the development of influenza virus-induced lung injury.
Availability of data and materials
Data sharing is offered under the format of collaborative projects. Proposals can be directed to the corresponding author.
Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. 2019;23:99.
Kenney AD, Li Z, Bian Z, Zhou X, Li H, Whitson BA, et al. Recombinant MG53 protein protects mice from lethal influenza virus infection. Am J Respir Crit Care Med. 2021;203:254–7.
Freuchet A, Salama A, Remy S, Guillonneau C, Anegon I. IL-34 and CSF-1, deciphering similarities and differences at steady state and in diseases. J Leukoc Biol. 2021. https://doi.org/10.1002/JLB.3RU1120-773R
Lin X, Luo H, Yan X, Song Z, Gao X, Xia Y, et al. Interleukin-34 ameliorates survival and bacterial clearance in polymicrobial sepsis. Crit Care Med. 2018;46:e584–90.
Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol. 2011;44:725–38.
We warmly acknowledge Dr Jun Duan, Dr Fang Xu, Dr Hongchun Luo, and all the residents who took care of the patients
This study was funded by the National Natural Science Foundation of China Grants (Nos. 81902134 and 81802079).
This study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University and written consent was obtained from participants.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Xu, B., Lin, X., Gong, Y. et al. Interleukin-34: an important modifier in the pathogenesis of influenza pneumonia. Crit Care 25, 274 (2021). https://doi.org/10.1186/s13054-021-03708-0