SerpinB2 is critical to Th2 immunity against enteric nematode infection

J Immunol. 2013 Jun 1;190(11):5779-87. doi: 10.4049/jimmunol.1200293. Epub 2013 Apr 29.

Abstract

SerpinB2, a member of the serine protease inhibitor family, is expressed by macrophages and is significantly upregulated by inflammation. Recent studies implicated a role for SerpinB2 in the control of Th1 and Th2 immune responses, but the mechanisms of these effects are unknown. In this study, we used mice deficient in SerpinB2 (SerpinB2(-/-)) to investigate its role in the host response to the enteric nematode, Heligmosomoides bakeri. Nematode infection induced a STAT6-dependent increase in intestinal SerpinB2 expression. The H. bakeri-induced upregulation of IL-4 and IL-13 expression was attenuated in SerpinB2(-/-) mice coincident with an impaired worm clearance. In addition, lack of SerpinB2 in mice resulted in a loss of the H. bakeri-induced smooth muscle hypercontractility and a significant delay in infection-induced increase in mucosal permeability. Th2 immunity is generally linked to a CCL2-mediated increase in the infiltration of macrophages that develop into the alternatively activated phenotype (M2). In H. bakeri-infected SerpinB2(-/-) mice, there was an impaired infiltration and alternative activation of macrophages accompanied by a decrease in the intestinal CCL2 expression. Studies in macrophages isolated from SerpinB2(-/-) mice showed a reduced CCL2 expression, but normal M2 development, in response to stimulation of Th2 cytokines. These data demonstrate that the immune regulation of SerpinB2 expression plays a critical role in the development of Th2-mediated protective immunity against nematode infection by a mechanism involving CCL2 production and macrophage infiltration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cytokines / immunology
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / parasitology
  • Intestines / immunology*
  • Intestines / parasitology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Monocytes / immunology
  • Monocytes / metabolism
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / parasitology
  • Nematode Infections / genetics
  • Nematode Infections / immunology*
  • Nematode Infections / metabolism*
  • Plasminogen Activator Inhibitor 2 / deficiency
  • Plasminogen Activator Inhibitor 2 / genetics
  • Plasminogen Activator Inhibitor 2 / metabolism*
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*

Substances

  • Cytokines
  • Plasminogen Activator Inhibitor 2