{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:46:47Z","timestamp":1793321207994,"version":"4.5.0"},"reference-count":73,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T00:00:00Z","timestamp":1732320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH), USA","award":["R21AI186028-01"],"award-info":[{"award-number":["R21AI186028-01"]}]},{"name":"National Institutes of Health (NIH), USA","award":["R01HL165423-01A1"],"award-info":[{"award-number":["R01HL165423-01A1"]}]},{"name":"National Institutes of Health (NIH), USA","award":["P30GM149368-02"],"award-info":[{"award-number":["P30GM149368-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>RNA virus-induced excessive inflammation and impaired antiviral interferon (IFN-I) responses are associated with severe disease. This innate immune response, also referred to as \u201cdysregulated immunity\u201d is caused by viral single-stranded RNA (ssRNA)- and double-stranded-RNA (dsRNA)-mediated exuberant inflammation and viral protein-induced IFN antagonism. However, key host factors and the underlying mechanism driving viral RNA-mediated dysregulated immunity are poorly defined. Here, using viral ssRNA and dsRNA mimics, which activate toll-like receptor 7 (TLR7) and TLR3, respectively, we evaluated the role of viral RNAs in causing dysregulated immunity. We observed that murine bone marrow-derived macrophages (BMDMs), when stimulated with TLR3 and TLR7 agonists, induced differential inflammatory and antiviral cytokine response. TLR7 activation triggered a robust inflammatory cytokine\/chemokine induction compared to TLR3 activation, whereas TLR3 stimulation induced significantly increased IFN\/IFN stimulated gene (ISG) response relative to TLR7 activation. To define the mechanistic basis for dysregulated immunity, we examined cell-surface and endosomal TLR levels and downstream mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kB) activation. We identified significantly higher cell-surface and endosomal TLR7 levels compared to TLR3, which were associated with early and robust MAPK (p-ERK1\/2, p-P38, and p-JNK) and NF-kB activation in TLR7-stimulated macrophages. Furthermore, blocking EKR1\/2 and NF-kB activity reduced TLR3\/7-induced inflammatory cytokine\/chemokine levels, whereas only ERK1\/2 inhibition enhanced viral RNA mimic-induced IFN\/ISG responses. Collectively, our results illustrate that high cell-surface and endosomal TLR7 expression and robust ERK1\/2 activation drive viral ssRNA mimic-induced excessive inflammatory and reduced IFN\/ISG response and blocking ERK1\/2 activity would likely mitigate viral-RNA\/TLR-induced dysregulated immunity.<\/jats:p>","DOI":"10.3390\/pathogens13121033","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T03:59:01Z","timestamp":1732507141000},"page":"1033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Differential TLR-ERK1\/2 Activity Promotes Viral ssRNA and dsRNA Mimic-Induced Dysregulated Immunity in Macrophages"],"prefix":"10.3390","volume":"13","author":[{"given":"Rakshya","family":"Shrestha","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7291-8290","authenticated-orcid":false,"given":"Paige Marie","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1397-3966","authenticated-orcid":false,"given":"Roshan","family":"Ghimire","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5675-701X","authenticated-orcid":false,"given":"Cody John","family":"Whitley","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudragouda","family":"Channappanavar","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"},{"name":"Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Abdelwhab, E.M., and Mettenleiter, T.C. 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