Dermatomyositis and anti-synthetase syndrome are commonly associated with ILD in clinical practice. The onset, clinical manifestations, progression, treatment response, and prognosis of IIM-ILD patients are heterogeneous, posing challenges in clinical diagnosis and treatment. Additionally, IIM-ILD is a significant cause of disability and mortality in IIM patients[13]. The pathogenesis of IIM-ILD is complex, and early blockade of inflammatory responses is crucial. IIM often affects tissues other than muscles, and the lungs are a commonly involved organ. However, the mechanisms underlying pulmonary interstitial abnormalities in IIM are not yet clear. Currently, glucocorticoids combined with immunosuppressive agents remain the preferred treatment in clinical practice for alleviating symptoms[14]. To further understand, diagnose, and treat this disease, there is an urgent need for a stable animal model and relevant therapeutic approaches.
There is cross-reactivity between rat skeletal muscle and BALB/c mouse skeletal muscle antigens. By inducing multiple injections after complete Freund’s adjuvant emulsification, tolerance to self-cross-reactive antigens in BALB/c mice can be disrupted, promoting the production of specific immune responses and the generation of muscle antibodies in vivo, leading to the occurrence of myositis[12]. The mechanism underlying the development of lung lesions in this process is currently unclear. Studies have shown that among the inflammatory cell infiltrates in all inflammatory myopathies, there is high expression of pro-inflammatory cytokines IFN-γ, IL-1β, TNF-α, and IL-6[15, 16].
Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the TEC family. BTK plays a crucial role in B-cell receptor (BCR) signaling by activating PLCγ and transmitting signals through downstream second messengers IP3 and DAG. Early events triggered by activated BCR signaling pathway activate downstream signaling molecules, including kinases and signaling pathways such as MAPK/ERK, AKT/mTOR, PKCβ, BCL10/CARD11/MALT1, and calcium influx. This leads to transcriptional activation mediated by factors such as NF-κB, MYC, and NFAT, ultimately promoting a series of cellular physiological activities including integrin activation, chemokine-mediated cell migration, B-cell proliferation, differentiation, and apoptosis[17]. In addition to its well-known role in BCR signaling, BTK also participates in downstream signaling of various Fc receptors in chemokine receptor, Toll-like receptor, NLRP3 inflammasome, and innate immune cells. Zanubrutinib is a small molecule tyrosine kinase inhibitor that effectively inhibits BTK and regulates B-cell function. B cells play an important role in connective tissue diseases (CTDs)[18] and interstitial lung diseases (ILDs)[19], including myositis-associated ILD (IIM-ILD). However, there have been no reports on the therapeutic effects of BTK inhibitors in CTD-ILD, specifically IIM-ILD.
We have compiled the previous research on anti-organ fibrosis drugs in our research group, as well as summarized the pharmacological and pathogenic mechanisms. Considering the alleviating effect of zanubrutinib on cardiac fibrosis[11], its protective effect on acute lung injury[9], and the alleviating effect of bortezomib-induced lung injury in mice[10], we ultimately discovered that zanubrutinib can effectively alleviate the progression of experimental IIM-ILD. To the best of our knowledge, this is the first evaluation of the dual inhibitory effect of a BTK inhibitor on both IIM and ILD in an IIM-related ILD animal model. Furthermore, we found that this dual inhibitory effect is achieved through the inhibition of BTK and NF-κB phosphorylation.
In summary, we have established a stable IIM-ILD animal model and discovered that a BTK inhibitor, zanubrutinib, can effectively alleviate symptoms in experimental IIM-ILD mice. We also found that zanubrutinib inhibits the phosphorylation of BTK and NF-κB in lung tissue. This provides a theoretical basis for clinical medication. Moving forward, we will focus on investigating the cellular targets, non-BTK proteins, and immunomodulatory effects of zanubrutinib in the context of IIM-ILD, aiming to further explore its pharmacological mechanism.