Premium
Pharmacological activation of Mac‐1 modulates TLR4 signal transduction pathways
Author(s) -
Stoub Darren,
Gupta Vineet
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb95
Subject(s) - signal transduction , phosphorylation , inflammation , tlr4 , trif , protein kinase b , microbiology and biotechnology , immunology , lupus nephritis , western blot , cancer research , chemistry , pharmacology , medicine , biology , immune system , toll like receptor , innate immune system , biochemistry , gene , disease
Mac‐1, a β2 integrin, has been implicated in leukocyte‐mediated inflammation and may be involved in the etiology of several diseases, such as serum nephritis and systemic lupus erythematosus. We recently reported the discovery of a novel class of small molecule Mac‐1 agonists, which elicit an anti‐inflammatory effect. Here, we report that LA1, one of our novel agonists, mitigates LPS‐induced inflammation by suppressing TLR4‐dependent pro‐inflammatory signalling in leukocytes. Specifically, LA1 treatment modulates phosphorylation of several relevant signal transduction proteins, as seen by western blot analaysis, and impacts cellular localization of FOX03 and NFkB, as seen through immunofluorescence. We suggest that activation of the alpha subunit of Mac‐1, CD11b, suppresses MyD88 activation, which impacts AKT and IKKα/β phosphorylation, thereby suppressing the production of IRF7, IL‐18 and IFN I. Our results suggest that activation of Mac‐1 may represent a novel mechanism for the treatment of several inflammatory diseases. Support or Funding Information Funding provided by Rush University Medical Center and Dordt College