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The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis

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Abstract

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts’ differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia.

Highlights

  • S100A8/A9 level is highly upregulated in the IPF patients’ lungs as well as the blood.

  • S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts.

  • The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts.

  • The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model.

Graphical abstract

In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region—which is provided mainly by the activated neutrophils and macrophages—exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1–3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

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Abbreviations

ALCAM:

Activated leukocyte cell adhesion molecule

α-SMA:

α-smooth muscle actin

BALF:

Bronchoalveolar lavage fluid

BLM:

Bleomycin

ECM:

Extracellular matrix

EMMPRIN:

Extracellular matrix metalloproteinase inducer

EMSA:

Electrophoretic mobility shift assay

GVHD:

Graft-versus-host disease

H&E:

Hematoxylin and eosin

HMGB1:

High-mobility group box1 protein

IHC:

Immunohistochemistry

IPF:

Idiopathic pulmonary fibrosis

LAM:

Lymphangioleiomyomatosis

MCAM:

Melanoma cell adhesion molecule

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NPTN:

Neuroplastin

PDAC:

Pancreatic ductal adenocarcinoma

PPH:

Primary pulmonary hypertension

RAGE:

Receptor for advanced glycation end products

SSSR:

S100 soil sensor receptor

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Acknowledgments

We thank Dr. Shin Morizane and Dr. Tomoko Miyake (Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences) for the preparation of the psoriasis patients’ skin tissue sections used herein as a representative positive control for evaluating the S100A8/A9 staining. We also gratefully acknowledge Dr. Seiichi Tanida (Advanced Science, Technology and Management Research Institute of Kyoto) and Dr. Michiaki Mishima (Kyoto University) for their critical advice to this study.

Funding

This research was supported by grants from the Acceleration Transformative Research for Medical Innovation (ACT-M) in the Japan Agency for Medical Research and Development (AMED) (no. JP20im0210119) and the JSPS KAKENHI (no. 17H03577 to M.S.; no 19H03746 to S.T.) and by funds to M.S. from the Smoking Research Foundation, the Terumo Life Science Foundation, and the Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Ken-ichi Yamamoto, Hitoshi Murata & Masakiyo Sakaguchi

  2. Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Kota Araki, Yuta Takahashi, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki & Shinichi Toyooka

  3. Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan

    Shuta Tomida

  4. Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Satoru Senoo

  5. Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan

    Akihiko Taniguchi, Junko Itano & Nobuaki Miyahara

  6. Department of Organ Transplant Center, Okayama University Hospital, Okayama, Japan

    Seiichiro Sugimoto

  7. Department of Pathology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan

    Kouichi Ichimura

  8. Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Masahiro Nishibori

  9. Department of Medical Technology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Nobuaki Miyahara

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  1. Kota Araki
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Contributions

K.A. established the methodology, designed and performed most of the experiments, and analyzed the data. R.K. prepared S100A8/A9 antibody and performed the ELISA and PCR experiments. N.T. and Y.G. assisted with most of the animal experiments and assisted K.A. in the data evaluation. S.T. contributed to the data analysis and its evaluation and validation. Y.T., S.S., K.S. K.S., H.Y. M. O., S.S., and K.I. contributed to the collection of the series of biomaterials. A.T. and N.M. contributed to the establishment of the animal model and assisted K.A. with some of the animal experiments. K.Y. and H.M. performed the primary cell culture and participated in the confirmation of some of the data of the in vitro cell assays. M.S. performed the immunoprecipitation, Western blot analysis, and EMSA, and M.N. assisted M.S.’s experiments. S.T and M.S. designed and supervised the project and wrote, reviewed, and edited the manuscript.

Corresponding authors

Correspondence to Shinichi Toyooka or Masakiyo Sakaguchi.

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The authors declare that they have no conflicts of interest.

A couple of studies using clinical specimens (tissues and blood samples) were approved by the Okayama Medical School and Hospital’s Research Ethics Committee. The approved numbers are as follows: # 1910-017 and # 1906-033. Informed consent was obtained from individual patients for the use of their materials. Experimental protocols required for the animal studies were approved by the Animal Experiment Committee at Okayama University. The approved numbers are as follows: # OKU-2018901 and # OKU-2019350.

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Araki, K., Kinoshita, R., Tomonobu, N. et al. The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. J Mol Med 99, 131–145 (2021). https://doi.org/10.1007/s00109-020-02001-x

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