Innate Immune Drivers of Musculoskeletal Fibrosis and Regeneration Across Organ Systems

Fibrosis and musculoskeletal regeneration are critically influenced by the innate immune system, which balances effective tissue repair against pathological scarring. Dysregulated innate immunity drives chronic fibrotic diseases and impairs organ function, while a precisely regulated innate response is essential for musculoskeletal regeneration. Although roles of neutrophils, macrophages, and dendritic cells have been studied, the specific innate immune mechanisms directing fibrosis versus regeneration remain incompletely understood, particularly across different organ systems.Recent work highlights the importance of innate immune cell phenotypes, neutrophil extracellular traps (NETs), and cytokine/chemokine signaling in tissue remodeling. However, most studies focus on single-organ fibrosis or general inflammation-fibrosis interactions, often overlooking the unique features of musculoskeletal tissues and translational challenges in targeting innate immunity for regenerative therapies. There is a pressing need to clarify how innate immune mechanisms, distinct from adaptive responses, drive fibrotic versus regenerative outcomes specifically in musculoskeletal contexts and how these insights can inform therapeutic development.This Research Topic aims to define innate immune determinants governing the balance between fibrosis and musculoskeletal regeneration, emphasizing mechanistic and translational studies that bridge basic discovery and therapeutic innovation. Prioritizing comparative and cross-tissue analyses, it will highlight how innate immune cell states, signaling networks, and microenvironmental cues uniquely influence musculoskeletal repair and fibrotic progression. Emphasis is placed on studies providing biological validation and addressing translational bottlenecks in modulating innate immunity for musculoskeletal disorders.While musculoskeletal tissues remain the primary focus, the Research Topic will also consider comparative studies from the lung and other organs when they reveal conserved or tissue-specific innate immune mechanisms relevant to musculoskeletal fibrosis and regeneration. Airway remodeling provides a useful comparative framework for examining how pathways such as Hedgehog signaling regulate innate immune-stromal interactions, inflammatory persistence, pathological scarring, and tissue repair.We invite contributions offering mechanistic insight into innate immune regulation of fibrosis and regeneration in musculoskeletal tissues. This includes cross-organ studies, including work on airway remodeling, when they provide direct comparative evidence or experimentally supported mechanistic or therapeutic insight applicable to musculoskeletal fibrosis or regeneration. Broad molecular or epigenetic studies of fibrosis lacking biological validation, generic inflammation-fibrosis interactions, or adaptive immune mechanisms, as well as airway, cardiac, or other organ-specific studies without an explicit musculoskeletal connection are outside scope.Topics of interest include, but are not limited to:- Mechanistic regulation by innate immune cell phenotypes and activation states (including neutrophils, macrophages, and dendritic cells) directing musculoskeletal fibrosis versus regeneration- Roles of neutrophil extracellular traps (NETs) and cytokine or chemokine signaling networks in shaping musculoskeletal tissue remodeling- Intercellular crosstalk between innate immune cells and resident musculoskeletal populations (e.g., myocytes, osteoblasts, chondrocytes, and fibroblasts) within fibrotic and regenerative niches- Comparative analyses of conserved and tissue-specific innate immune-stromal pathways across musculoskeletal and non-musculoskeletal systems, including Hedgehog-mediated airway remodeling, that provide direct mechanistic insight into musculoskeletal repair- Pharmacological modulation of innate immune-stromal signaling to prevent pathological fibrosis and enhance musculoskeletal regeneration, including target validation, mechanism of action, and exposure-response relationships- Translational challenges, therapeutic timing, and delivery strategies for modulating innate immunity in musculoskeletal disorders- Preclinical validation of innate immune-targeted therapeutics and biologics in robust musculoskeletal disease and tissue-regeneration models Topic editors: Jasmin Knopf, Anthony Tam, Luke O'Neill, Stephen Geoffrey Ward Source: https://www.frontiersin.org/research-topics/86148/innate-immune-drivers-of-musculoskeletal-fibrosis-and-regeneration-across-organ-systems