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

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 m...

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Published in:	Frontiers in immunology Vol. 13; p. 1044662
Main Authors:	Owen, Allison M, Luan, Liming, Burelbach, Katherine R, McBride, Margaret A, Stothers, Cody L, Boykin, Olivia A, Sivanesam, Kalkena, Schaedel, Jessica F, Patil, Tazeen K, Wang, Jingbin, Hernandez, Antonio, Patil, Naeem K, Sherwood, Edward R, Bohannon, Julia K
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 11-11-2022
Subjects:	Adaptor Proteins, Signal Transducing - metabolism Adaptor Proteins, Vesicular Transport - metabolism Animals Humans Immunology innate immunity macrophage Macrophages metabolic reprogramming Mice Myeloid Differentiation Factor 88 - metabolism TLR4 toll-like receptor (TLR) Toll-Like Receptor 4 - metabolism Toll-Like Receptors - metabolism trained immunity innate immunity innate immune memory macrophage toll-like receptor (TLR) trained immunity MyD88 TLR4 metabolic reprogramming
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Summary:	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 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 . 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Shih-Chin James Cheng, Xiamen University, China; Elba Mónica Vermeulen, Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria (CONICET), Argentina This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology Edited by: Liwu Li, Virginia Tech, United States
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2022.1044662