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Physical cues such as stretch, tissue stiffness, and shear stress shape innate immune responses across barrier epithelia, stromal niches, and the vascular endothelium. By engaging conserved mechanotransduction pathways, these forces both modulate and initiate mechano-inflammatory programs, remodeling immune synapses, reconfiguring tissue architecture, and directing leukocyte trafficking. When tissue mechanics are chronically perturbed through sustained pressure, matrix remodeling, or disturbed flow, these same pathways drive pathological inflammation and contribute to diseases ranging from asthma and arthritis to fibrotic disorders and atherosclerosis. In this review, we position mechano-inflammation as a unifying framework linking physical forces to immune regulation. We also highlight diagnostic and therapeutic opportunities targeting the mechanical dimension of immunity.<\/jats:p>","DOI":"10.1084\/jem.20252269","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:21:02Z","timestamp":1779344462000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanobiology of inflammation: Pulling the strings of innate immunity"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9815-8923","authenticated-orcid":true,"given":"Marcin Krzysztof","family":"Maniak","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wcr1b38","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh 1 , Edinburgh,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0233-5424","authenticated-orcid":true,"given":"Stephen J.","family":"Jenkins","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wcr1b38","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh 1 , Edinburgh,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0746-7482","authenticated-orcid":true,"given":"Carsten Gram","family":"Hansen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wcr1b38","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh 1 , Edinburgh,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"2026062309590849700_bib1","doi-asserted-by":"publisher","first-page":"3250","DOI":"10.1096\/fj.07-8218com","article-title":"Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis","volume":"21","author":"Aarabi","year":"2007","journal-title":"FASEB J."},{"key":"2026062309590849700_bib2","doi-asserted-by":"publisher","first-page":"120715","DOI":"10.1016\/j.biomaterials.2021.120715","article-title":"Substrate stiffness induces neutrophil extracellular trap (NET) formation through focal adhesion kinase activation","volume":"271","author":"Abaricia","year":"2021","journal-title":"Biomaterials"},{"key":"2026062309590849700_bib3","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf2675","article-title":"A Thy-1\u2013negative immunofibroblast population emerges as a key determinant of fibrotic outcomes to biomaterials","volume":"10","author":"Abebayehu","year":"2024","journal-title":"Sci. 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