Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis

Daniel P. Zachs; Sarah J. Offutt; Rachel S. Graham; Yohan Kim; Jerel Mueller; Jennifer L. Auger; Nathaniel J. Schuldt; Claire R. W. Kaisers; Abigail P. Heiiler; Raini Dutta; Hongsun Guo; Jamu K. Alford; Bryce A. Binstadt; Hubert H. Lim

doi:10.1038/s41467-019-08721-0

Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis

Daniel P. Zachs, Sarah J. Offutt, Rachel S. Graham, Yohan Kim, Jerel Mueller, Jennifer L. Auger, Nathaniel J. Schuldt, Claire R. W. Kaisers, Abigail P. Heiiler, Raini Dutta, Hongsun Guo, Jamu K. Alford, Bryce A. Binstadt, Hubert H. Lim

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

Original language	English
Article number	951
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08721-0
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
Due to the unique potential of US to provide a noninvasive, non-pharmacological approach to treating inflammatory diseases, as well as the consistency in results across studies between two independent research groups, we have initiated a pilot clinical trial (Clin-icalTrials.gov Identifier: NCT03690466) funded by the United States Defense Advanced Research Projects Agency (DARPA) to explore the use of US as an alternative therapy for human patients with rheumatoid arthritis. Positive findings from this clinical trial, combined with the encouraging data presented in these companion papers, will open new opportunities for applying US of peripheral nerves and end-organs to treat a range of chronic inflammatory diseases, such as rheumatoid arthritis and other health conditions.

Funding Information:
We thank Cory Gloeckner, Tianqi Li, John Basile, Gerardo Rodriguez, Mark Hamilton, and Alyona Haritonova for their assistance with the project. We also thank Erik Peterson, whose guidance on the project’s clinical relevance was much appreciated. This work was supported by the United States Defense Advanced Research Projects Agency (DARPA) Electrical Prescriptions (ElectRx) Program (DARPA BTO HR0011-16C-0014) under the auspices of Doug Weber and Eric Van Gieson, with additional support from Gretchen Knaack, Tyler Best, and Rebekah Cecil at DARPA. The views, opinions and/or findings expressed are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government.

Publisher Copyright:
© 2019, The Author(s).

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Journal Article

Publisher link

10.1038/s41467-019-08721-0

Find It

Find It at U of M Libraries

Cite this

Zachs, D. P., Offutt, S. J., Graham, R. S., Kim, Y., Mueller, J., Auger, J. L., Schuldt, N. J., Kaisers, C. R. W., Heiiler, A. P., Dutta, R., Guo, H., Alford, J. K., Binstadt, B. A., & Lim, H. H. (2019). Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis. Nature communications, 10(1), Article 951. https://doi.org/10.1038/s41467-019-08721-0

@article{79cbf5da1fde40198592ec61f8c1b0bd,

title = "Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis",

abstract = "Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.",

author = "Zachs, {Daniel P.} and Offutt, {Sarah J.} and Graham, {Rachel S.} and Yohan Kim and Jerel Mueller and Auger, {Jennifer L.} and Schuldt, {Nathaniel J.} and Kaisers, {Claire R. W.} and Heiiler, {Abigail P.} and Raini Dutta and Hongsun Guo and Alford, {Jamu K.} and Binstadt, {Bryce A.} and Lim, {Hubert H.}",

note = "Funding Information: Due to the unique potential of US to provide a noninvasive, non-pharmacological approach to treating inflammatory diseases, as well as the consistency in results across studies between two independent research groups, we have initiated a pilot clinical trial (Clin-icalTrials.gov Identifier: NCT03690466) funded by the United States Defense Advanced Research Projects Agency (DARPA) to explore the use of US as an alternative therapy for human patients with rheumatoid arthritis. Positive findings from this clinical trial, combined with the encouraging data presented in these companion papers, will open new opportunities for applying US of peripheral nerves and end-organs to treat a range of chronic inflammatory diseases, such as rheumatoid arthritis and other health conditions. Funding Information: We thank Cory Gloeckner, Tianqi Li, John Basile, Gerardo Rodriguez, Mark Hamilton, and Alyona Haritonova for their assistance with the project. We also thank Erik Peterson, whose guidance on the project{\textquoteright}s clinical relevance was much appreciated. This work was supported by the United States Defense Advanced Research Projects Agency (DARPA) Electrical Prescriptions (ElectRx) Program (DARPA BTO HR0011-16C-0014) under the auspices of Doug Weber and Eric Van Gieson, with additional support from Gretchen Knaack, Tyler Best, and Rebekah Cecil at DARPA. The views, opinions and/or findings expressed are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-08721-0",

language = "English",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis

AU - Zachs, Daniel P.

AU - Offutt, Sarah J.

AU - Graham, Rachel S.

AU - Kim, Yohan

AU - Mueller, Jerel

AU - Auger, Jennifer L.

AU - Schuldt, Nathaniel J.

AU - Kaisers, Claire R. W.

AU - Heiiler, Abigail P.

AU - Dutta, Raini

AU - Guo, Hongsun

AU - Alford, Jamu K.

AU - Binstadt, Bryce A.

AU - Lim, Hubert H.

N1 - Funding Information: Due to the unique potential of US to provide a noninvasive, non-pharmacological approach to treating inflammatory diseases, as well as the consistency in results across studies between two independent research groups, we have initiated a pilot clinical trial (Clin-icalTrials.gov Identifier: NCT03690466) funded by the United States Defense Advanced Research Projects Agency (DARPA) to explore the use of US as an alternative therapy for human patients with rheumatoid arthritis. Positive findings from this clinical trial, combined with the encouraging data presented in these companion papers, will open new opportunities for applying US of peripheral nerves and end-organs to treat a range of chronic inflammatory diseases, such as rheumatoid arthritis and other health conditions. Funding Information: We thank Cory Gloeckner, Tianqi Li, John Basile, Gerardo Rodriguez, Mark Hamilton, and Alyona Haritonova for their assistance with the project. We also thank Erik Peterson, whose guidance on the project’s clinical relevance was much appreciated. This work was supported by the United States Defense Advanced Research Projects Agency (DARPA) Electrical Prescriptions (ElectRx) Program (DARPA BTO HR0011-16C-0014) under the auspices of Doug Weber and Eric Van Gieson, with additional support from Gretchen Knaack, Tyler Best, and Rebekah Cecil at DARPA. The views, opinions and/or findings expressed are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

AB - Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

UR - http://www.scopus.com/inward/record.url?scp=85062892063&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062892063&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-08721-0

DO - 10.1038/s41467-019-08721-0

M3 - Article

C2 - 30862842

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 951

ER -

Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis

Abstract

Bibliographical note

PubMed: MeSH publication types

Publisher link

Find It

Other files and links

Fingerprint

Cite this