Th2 cells and macrophages cooperatively induce allergic inflammation through histamine signaling

PLoS One. 2021 Mar 4;16(3):e0248158. doi: 10.1371/journal.pone.0248158. eCollection 2021.


Histamine, which is mainly produced by mast cells and basophils, participates in various allergic symptoms, and some studies have reported that macrophages also produce histamine. Moreover, recent studies have revealed that macrophages, especially alternatively activated macrophages (M2) induced by T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, participate in the pathogenesis of allergic diseases. The major source of Th2 cytokines is antigen-specific Th2 cells. To elucidate the relationship between histamine, macrophages, and Th2 cells in allergic inflammation, we established a macrophage-Th2 cell co-culture model in vitro and an antigen-specific Th2 cell transfer mouse model of rhinitis. In vitro analyses indicated that macrophages produce histamine by interacting with antigen-specific Th2 cells through the antigen. Furthermore, Th2 cells and macrophages cooperatively elicited rhinitis in the mouse model. We determined that histamine induces Th2- and macrophage-elicited sneezing responses through H1 receptor signaling, whereas it induces nasal eosinophil infiltrations through H4 receptor signaling. Collectively, these results indicate a novel histamine production mechanism by macrophages, in which Th2 cells and macrophages cooperatively induce nasal allergic inflammation through histamine signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Histamine / immunology*
  • Humans
  • Inflammation / immunology*
  • Inflammation / pathology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Mice
  • Mice, Inbred BALB C
  • Rhinitis, Allergic / immunology*
  • Rhinitis, Allergic / pathology
  • Signal Transduction
  • Th2 Cells / immunology*
  • Th2 Cells / pathology


  • Histamine

Grant support

NI received a Japan Society for the Promotion of Science ( KAKENHI Grant-in-Aid for Young Scientists (Grant Number 19K17912) and a GlaxoSmithKline Japan ( Research Grant 2017. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.