Skip to main content

ORIGINAL RESEARCH article

Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1456042
This article is part of the Research Topic Genes, Cells, and Macroenvironments: Regulating the Immune Response in Extreme Conditions View all articles

Synergetic Role of TRPV4 Inhibitor and Mechanical Loading on Reducing Inflammation

Provisionally accepted
Parto Babaniamansour Parto Babaniamansour 1Diego Jacho Diego Jacho 1Agustin Rabino Agustin Rabino 2Rafael Garcia-Mata Rafael Garcia-Mata 2Eda Yildirim Eda Yildirim 1*
  • 1 University of Toledo, Toledo, United States
  • 2 University of Toledo Medical Center, Toledo, Ohio, United States

The final, formatted version of the article will be published soon.

    Resolution of inflammation is essential for normal tissue healing and regeneration, with macrophages playing a key role in regulating this process through phenotypic changes from a pro-inflammatory to an anti-inflammatory state. Pharmacological and mechanical (mechanotherapy) techniques can be employed to polarize macrophages toward an antiinflammatory phenotype, thereby diminishing inflammation. One clinically relevant pharmacological approach is the inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4). This study investigates the effects of various mechanical loading amplitudes (0%, 3%, and 6%) and TRPV4 inhibition (10 µM RN-1734) on the phenotypic commitments of pro-inflammatory (M1) macrophages within three-dimensional (3D) collagen matrices. M1 macrophages exposed to 3% mechanical strain exhibited upregulated pro-inflammatory responses, including increased proinflammatory gene expression and enhanced proteolytic activity within the extracellular matrix. TRPV4 inhibition partially mitigated this inflammation. Notably, 6% mechanical strain combined with TRPV4 inhibition suppressed Mitogen-Activated Protein Kinase (MAPK) expression, leading to reduced pro-inflammatory gene expression and increased anti-inflammatory markers such as CD206. Gene expression analysis further demonstrated significant reductions in pro-inflammatory gene expression and a synergistic promotion of anti-inflammatory phenotypes under TRPV4 inhibition at 6% mechanical strain. Surface protein analysis via immunohistochemistry confirmed these phenotypic shifts, highlighting changes in the expression of CD80 (pro-inflammatory) and CD206 (anti-inflammatory) markers, alongside F-actin and nuclear staining. This research suggests that TRPV4 inhibition, combined with specific mechanical loading (6%), can drive macrophages toward an anti-inflammatory state, thereby may promote inflammation resolution and tissue repair.

    Keywords: transient receptor potential vanilloid 4 (TRPV4), inhibition, mechanical loading, Macrophage polarization, pro-inflammatory (M1) macrophages, anti-inflammatory phenotype

    Received: 27 Jun 2024; Accepted: 04 Dec 2024.

    Copyright: © 2024 Babaniamansour, Jacho, Rabino, Garcia-Mata and Yildirim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Eda Yildirim, University of Toledo, Toledo, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.