The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection

Cell Rep. 2024 Feb 27;43(2):113795. doi: 10.1016/j.celrep.2024.113795. Epub 2024 Feb 15.


Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2-/- mice are only slightly susceptible to T. gondii infection, similar to Irak1-/- mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo.

Keywords: CP: Immunology; CP: Microbiology; IL-12; IRAK; IRF5; Toll-like receptors; Toxoplasma gondii; cell signaling; dendritic cells; innate immunity; monocytes; myddosome.

MeSH terms

  • Animals
  • Dendritic Cells
  • Interferon Regulatory Factors / genetics
  • Interleukin-1 Receptor-Associated Kinases*
  • Interleukin-12
  • Mice
  • Toxoplasmosis*


  • Interferon Regulatory Factors
  • Interleukin-1 Receptor-Associated Kinases
  • Interleukin-12
  • Irf5 protein, mouse
  • Irak1 protein, mouse