Myxoma viral serpin, serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B

Kasinath Viswanathan, Jakob Richardson, Babajide Togonu-Bickersteth, Erbin Dai, Liying Liu, Pracha Vatsya, Yun Ming Sun, Jeff Yu, Ganesh Munuswamy-Ramanujam, Henry Baker, Alexandra R. Lucas

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Serp-1 is a secreted myxoma viral serine protease inhibitor (serpin) with proven, highly effective, anti-inflammatory defensive activity during host cell infection, as well as potent immunomodulatory activity in a wide range of animal disease models. Serp-1 binds urokinase-type plasminogen activator (uPA) and the tissue-type PA, plasmin, and factor Xa, requiring uPA receptor (uPAR) for anti-inflammatory activity. To define Serp-1-mediated effects on inflammatory cell activation, we examined the association of Serp-1 with monocytes and T cells, effects on cellular migration, and the role of uPAR-linked integrins and actin-binding proteins in Serp-1 cellular responses. Our results show that Serp-1 associates directly with activated monocytes and T lymphocytes, in part through interaction with uPAR (P<0.001). Serp-1, but not mammalian serpin PA inhibitor-1 (PAI-1), attenuated cellular adhesion to the extracellular matrix. Serp-1 and PAI-1 reduced human monocyte and T cell adhesion (P<0.001) and migration across endothelial monolayers in vitro (P< 0.001) and into mouse ascites in vivo (P<0.001). Serp-1 and an inactive Serp-1 mutant Serp-1(SAA) bound equally to human monocytes and T cells, but a highly proinflammatory mutant, Serp-1(Ala 6), bound less well to monocytes. Serp-1 treatment of monocytes increased expression of filamin B actin-binding protein and reduced CD18 (P-integrin) expression (P< 0.001) in a uPAR-dependent response. Filamin colocalized and coimmunoprecipitated with uPAR, and short interference RNA knock-down of filamin blocked Serp-1 inhibition of monocyte adhesion. We report here that the highly potent, anti-inflammatory activity of Serp-1 is mediated through modification of uPAR-linked β-integrin and filamin in monocytes, identifying this interaction as a central regulatory axis for inflammation.

Original languageEnglish (US)
Pages (from-to)418-426
Number of pages9
JournalJournal of Leukocyte Biology
Volume85
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Keywords

  • Inflammation
  • Macrophage
  • Thrombolysis
  • Virus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Myxoma viral serpin, serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B'. Together they form a unique fingerprint.

Cite this