Serum IgA Immune Complexes Promote Proinflammatory Cytokine Production by Human Macrophages, Monocytes, and Kupffer Cells Through FcαRI-TLR Cross-Talk

J Immunol. 2017 Dec 15;199(12):4124-4131. doi: 10.4049/jimmunol.1700883. Epub 2017 Nov 8.

Abstract

IgA is predominantly recognized to play an important role in host defense at mucosal sites, where it prevents invasion of pathogens by neutralization. Although it has recently become clear that IgA also mediates other immunological processes, little remains known about the potential of IgA to actively contribute to induction of inflammation, particularly in nonmucosal organs and tissues. In this article, we provide evidence that immune complex formation of serum IgA plays an important role in orchestration of inflammation in response to pathogens at various nonmucosal sites by eliciting proinflammatory cytokines by human macrophages, monocytes, and Kupffer cells. We show that opsonization of bacteria with serum IgA induced cross-talk between FcαRI and different TLRs, leading to cell type-specific amplification of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-23. Furthermore, we demonstrate that the increased protein production of cytokines was regulated at the level of gene transcription, which was dependent on activation of kinases Syk and PI3K. Taken together, these data demonstrate that the immunological function of IgA is substantially more extensive than previously considered and suggest that serum IgA-induced inflammation plays an important role in orchestrating host defense by different cell types in nonmucosal tissues, including the liver, skin, and peripheral blood.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Antibody Complex / immunology*
  • Antigens, CD / immunology*
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Enzyme Activation
  • Humans
  • Immunoglobulin A / blood
  • Immunoglobulin A / immunology*
  • Inflammation / etiology
  • Inflammation / immunology*
  • Kupffer Cells / immunology*
  • Macrophages / immunology*
  • Monocytes / immunology*
  • Opsonin Proteins / immunology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptor Cross-Talk / immunology*
  • Receptors, Fc / immunology*
  • Syk Kinase / metabolism
  • Toll-Like Receptors / immunology*
  • Transcription, Genetic

Substances

  • Antigen-Antibody Complex
  • Antigens, CD
  • Cytokines
  • Fc(alpha) receptor
  • Immunoglobulin A
  • Opsonin Proteins
  • Receptors, Fc
  • Toll-Like Receptors
  • Phosphatidylinositol 3-Kinases
  • SYK protein, human
  • Syk Kinase