MyD88-dependent signaling drives toll-like receptor-induced trained immunity in macrophages

Front Immunol. 2022 Nov 11:13:1044662. doi: 10.3389/fimmu.2022.1044662. eCollection 2022.


Immunocompromised populations are highly vulnerable to developing life-threatening infections. Strategies to protect patients with weak immune responses are urgently needed. Employing trained immunity, whereby innate leukocytes undergo reprogramming upon exposure to a microbial product and respond more robustly to subsequent infection, is a promising approach. Previously, we demonstrated that the TLR4 agonist monophosphoryl lipid A (MPLA) induces trained immunity and confers broad resistance to infection. TLR4 signals through both MyD88- and TRIF-dependent cascades, but the relative contribution of each pathway to induction of trained immunity is unknown. Here, we show that MPLA-induced resistance to Staphylococcus aureus infection is lost in MyD88-KO, but not TRIF-KO, mice. The MyD88-activating agonist CpG (TLR9 agonist), but not TRIF-activating Poly I:C (TLR3 agonist), protects against infection in a macrophage-dependent manner. MPLA- and CpG-induced augmentation of macrophage metabolism and antimicrobial functions is blunted in MyD88-, but not TRIF-KO, macrophages. Augmentation of antimicrobial functions occurs in parallel to metabolic reprogramming and is dependent, in part, on mTOR activation. Splenic macrophages from CpG-treated mice confirmed that TLR/MyD88-induced reprogramming occurs in vivo. TLR/MyD88-triggered metabolic and functional reprogramming was reproduced in human monocyte-derived macrophages. These data show that MyD88-dependent signaling is critical in TLR-mediated trained immunity.

Keywords: MyD88; TLR4; innate immune memory; innate immunity; macrophage; metabolic reprogramming; toll-like receptor (TLR); trained immunity.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Humans
  • Macrophages
  • Mice
  • Myeloid Differentiation Factor 88* / metabolism
  • Toll-Like Receptor 4* / metabolism
  • Toll-Like Receptors / metabolism


  • Myeloid Differentiation Factor 88
  • Toll-Like Receptor 4
  • Adaptor Proteins, Vesicular Transport
  • Toll-Like Receptors
  • Adaptor Proteins, Signal Transducing
  • Myd88 protein, mouse