HIF-1α and MIF Enhance Neutrophil-Driven Type 3 Immunity and Chondrogenesis in a Murine Spondyloarthritis Model

Rheumatology and Immunology Medicine Biochemistry Life Sciences Immunology
hypoxia-inducible factor-1 alpha macrophage migration inhibitory factor neutrophil spondyloarthritis chondrogenesis cytokine STAT3

Research Background and Research Questions

Spondyloarthritis (SpA) is a typical disease characterized by type 3 immune-driven inflammation and new bone formation (NBF). Although previous studies have shown that Macrophage Migration Inhibitory Factor (MIF) plays a key role in the pathogenesis of SpA, its interactions with other molecules and specific mechanisms remain unclear. Research has clearly revealed that MIF can exacerbate inflammation in SpA by amplifying type 3 immune responses, but its related networks and synergistic particles are yet to be explored.

Research Source

This study was jointly conducted by researchers from multiple institutions, including Akihiro Nakamura, Sungsin Jo, Sayaka Nakamura, and others from the Schroeder Arthritis Institute, University Health Network, Toronto, and Hanyang University Institute for Rheumatology Research. The paper was published in “Cellular & Molecular Immunology” Volume 21, pages 770-786, 2024.

Research Process

The research was mainly divided into several steps: 1. MIF-related protein screening: Through the Integrative Interactions Database (IID), 172 proteins that can interact with MIF were identified in humans. In the comparison of joint tissues between SpA patients and healthy controls, HIF1A (Hypoxia-Inducible Factor-1α) was found to be significantly elevated in the joint tissues of SpA patients.

  1. Verification of MIF and HIF1A interaction: The physical interaction between MIF and HIF1A was confirmed in humans using co-immunoprecipitation. Additionally, enhanced HIF1A expression was validated in SpA patient joint sites through immunohistochemistry.

  2. HIF1A interacts with MIF in neutrophils: In mouse models, the interaction between MIF and HIF1A in neutrophils was further demonstrated through immunohistochemistry and flow cytometry. In both mice and humans, HIF1A and MIF play key roles in the expression of type 3 immune-related cytokines such as IL23.

  3. Application of HIF1A inhibitor PX-478: Further studies showed that the use of the HIF1A selective inhibitor (PX-478) significantly alleviated symptoms of SpA in mice and significantly reduced the expression levels of MIF and IL-23.

  4. Genetic deletion experiments: In MIF-deficient mice, the study found that despite the presence of psoriasis-like dermatitis and blepharitis, joint inflammation and new bone formation were absent, thus proving the critical role of MIF and HIF1A inhibition in inflammation and new bone formation.

Main Research Findings

  1. Interaction between MIF and HIF1A: The study screened several key proteins interacting with MIF, including HIF1A, through protein interaction databases. In mouse models, HIF1A levels were significantly increased at inflammatory sites and formed interactions with MIF.

  2. HIF1A drives IL-23 production in hypoxia-induced neutrophils: Under hypoxic conditions, neutrophils showed a significant increase in MIF and IL-23 expression. This increase was greatly attenuated after using the HIF1A inhibitor PX-478.

  3. Therapeutic potential of PX-478: In mouse models, the use of PX-478 significantly reduced inflammatory responses and new bone formation from the early stages of inflammation. PX-478 not only plays a role in inhibiting type 3 immune responses but also affects chondrogenesis by inhibiting HIF1A.

Conclusions and Research Significance

This study clearly demonstrates that HIF1A is a key molecule that amplifies type 3 immune responses through interaction with MIF, thus playing an important role in the pathophysiology of SpA. By inhibiting HIF1A, type 3 immune-mediated inflammation and new bone formation can be effectively alleviated, providing new insights for future treatments.

Highlights

  1. Discovery of the key role of HIF1A in MIF-driven pathology of gouty arthritis.
  2. Validation of HIF1A interacting with MIF in hypoxic environments to promote IL-23 expression, thereby enhancing type 3 immune responses.
  3. Demonstration of the significant effect of HIF1A inhibitor PX-478 in reducing inflammation and new bone formation through gene knockout and drug inhibition studies.
  4. First provision of clear evidence for HIF1A as a novel targeted molecule for treating SpA, and exploration of its dual role in immune regulation and chondrogenesis.

Research Significance and Application Value

This study not only provides a new molecular mechanism for SpA but also validates the potential efficacy of the HIF1A inhibitor PX-478, suggesting its possible use in precise treatment of SpA and similar related diseases. This opens up new directions and methods for future treatment of SpA.