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Dysregulation of IL-34 ligation to SDC-1 mitigates collagen-induced arthritis

Cellular & Molecular Immunology volume 19, pages 1070–1072 (2022)Cite this article

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IL-34 is a novel biomarker for rheumatoid arthritis (RA), as its serum levels are linked to C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor (RF), IL-6 and radiographic progression [1, 2]. IL-34 reprograms naïve circulating M0 cells into glycolytic (CD14+CD86+GLUT1high) M34 macrophages (MΦs) by binding to its pathogenic receptor, SDC-1, which controls the activation of its coreceptor/M-CSFR [3]. Glycolytic M34 MΦs are primed to differentiate into osteoclasts through SDC-1 ligation [3]. More importantly, IL-34 and SDC-1 are druggable targets, and the blockade of SDC-1 function is being developed for multiple myeloma [4].

Interestingly, in RA M34 MΦs, proinflammatory rewiring was accompanied by the induction of IL-1β, IL-6, TNF, CCL2, and CXCL8 along with a reduction in IL-103. Nonetheless, in IL-34-induced arthritis, in which the acute inflammatory network is controlled by F480+iNOS+ joint cells, the modest increase in TGFβ levels was negated in T cell-deficient mice compared to wt mice. These data indicate that in acute and chronic IL-34-mediated arthritis, F480+iNOS+ MΦs are common master regulators that can rebalance effector and regulatory T cells (Tregs). Others have shown that IL-34-differentiated monocytes display a protolerogenic phenotype that amplifies Tregs via TGFβ secretion [5].

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Fig. 1: CIA is alleviated in IL-34−/− and SDC-1−/− mice compared to the control animals.

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Acknowledgements

The authors would like to thank Balaji B. Ganesh, Director of the Flow Cytometry Core at the University of Illinois at Chicago, and Pei-Yu Wu for their excellent scientific advice. We thank Drs. Alexander and Colonna for kindly providing us with SDC-1−/− and IL-34−/− mice.

Funding

This work was supported in part by awards from the Department of Veteran’s Affairs MERIT Award BX002286, the Innovative Research Award from the Rheumatology Research Foundation (RRF), the National Institutes of Health NIH AI147697, the National Psoriasis Foundation (NPF), the Pfizer Investigator-Initiated Research (IIR) Program and the Chicago Biomedical Consortium (CBC) Accelerator Award.

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Authors and Affiliations

  1. Jesse Brown VA Medical Center, Chicago, IL, USA

    Anja Meyer, Ryan Sienes, Katrien van Raemdonck, Karol Palasiewicz & Shiva Shahrara

  2. Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, Chicago, IL, USA

    Anja Meyer, Katrien van Raemdonck, Karol Palasiewicz & Shiva Shahrara

  3. Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL, USA

    Brian Zanotti & Michael V. Volin

  4. Department of Orthopedic Surgery, The University of Illinois at Chicago, Chicago, IL, USA

    Daniel P. Mass

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  1. Anja Meyer
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  8. Shiva Shahrara
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Contributions

AM, KvR, and SS made substantial contributions to the study concept and design. AM, RS, BZ, KvR, KP, MVV, and SS contributed to data acquisition. AM, RS, BZ, KvR, KP, DPM, MVV, and SS contributed to the analysis and interpretation of the data. AM, RS, BZ, KvR, KP, DPM, MVV, and SS drafted the article or revised it critically for important intellectual content. AM, RS, BZ, KvR, KP, DPM, MVV, and SS approved the final version to be published. AM, RS, BZ, KvR, KP, DPM, MVV, and SS agree to the accountability for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SS had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Shiva Shahrara.

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The authors declare no competing interests.

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Meyer, A., Sienes, R., Zanotti, B. et al. Dysregulation of IL-34 ligation to SDC-1 mitigates collagen-induced arthritis. Cell Mol Immunol 19, 1070–1072 (2022). https://doi.org/10.1038/s41423-022-00886-x

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