bims-traimu 2022-12-04 papers

Issue of 2022‒12‒04
three papers selected by
Yantong Wan
Southern Medical University

Front Immunol. 2022 ;13 1044662

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

Allison M Owen, Liming Luan, Katherine R Burelbach, Margaret A McBride, Cody L Stothers, Olivia A Boykin, Kalkena Sivanesam, Jessica F Schaedel, Tazeen K Patil, Jingbin Wang, Antonio Hernandez, Naeem K Patil, Edward R Sherwood, Julia K Bohannon.

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

DOI: https://doi.org/10.3389/fimmu.2022.1044662

Nat Immunol. 2022 Dec 01.

Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.

Mangalakumari Jeyanathan, Maryam Vaseghi-Shanjani, Sam Afkhami, Jensine A Grondin, Alisha Kang, Michael R D'Agostino, Yushi Yao, Shreya Jain, Anna Zganiacz, Zachary Kroezen, Meera Shanmuganathan, Ramandeep Singh, Anna Dvorkin-Gheva, Philip Britz-McKibbin, Waliul I Khan, Zhou Xing.

Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.

DOI: https://doi.org/10.1038/s41590-022-01354-4

Arterioscler Thromb Vasc Biol. 2022 Dec 01.

Differential Expression of Inflammarafts in Macrophage Foam Cells and in Nonfoamy Macrophages in Atherosclerotic Lesions.

Juliana M Navia-Pelaez, Colin Agatisa-Boyle, Soo-Ho Choi, Yi Sak Kim, Shenglin Li, Elena Alekseeva, Kimberly Weldy, Yury I Miller.

BACKGROUND: Reprogramming of monocytes and macrophage manifests in hyperinflammatory responses and chronification of inflammation in atherosclerosis. Recent studies focused on epigenetic, transcriptional, and metabolic alterations that characterize trained immunity. However, the underlying effector mechanisms driving the hyperinflammatory response of reprogrammed macrophages remain unclear. We hypothesized that the plasma membrane of atherosclerotic lesion macrophages undergoes reprogramming to maintain inflammarafts, enlarged lipid rafts (LR) serving as a platform for assembly of inflammatory receptor complexes.METHODS: Single-cell suspensions from the aortae of Western diet-fed Ldlr-/- mice were gated for BODIPY-high foamy and BODIPY-low nonfoamy F4/80 macrophages by flow cytometry. Inflammarafts were characterized by increased levels of LR, TLR4 localization to LR, TLR4 dimers, and the proximity between TLR2, TLR1, and CD36. In a cellular model of trained immunity, LR, TLR4 dimers, and the inflammatory response were measured in bone marrow-derived macrophages subjected to a 24-hour treatment with lipopolysaccharide or OxLDL, followed by a 6-day wash-out period.
RESULTS: Nonfoamy macrophages, which constituted ≈40% of macrophages in atherosclerotic lesions, expressed significantly higher levels of LR and TLR4 dimers, as well as proximity ligation signals for TLR4-LR, TLR2-CD36, and TLR2-TLR1 complexes, compared with foamy macrophages. These inflammaraft measures associated, to a different degree, with plasma cholesterol and inflammatory cytokines, as well as the size of the atherosclerotic lesions and necrotic cores. The bone marrow-derived macrophages trained with lipopolysaccharide simulated nonfoamy atherosclerotic lesion macrophages and continued to express inflammarafts and inflammatory genes for 6 days after lipopolysaccharide removal and displayed a hyperinflammatory response to Pam3CSK4, a TLR2/TLR1 agonist. OxLDL-exposed, lipid-laden macrophages did not express inflammarafts.
CONCLUSIONS: Our data support the hypothesis that persistent inflammarafts in nonfoamy macrophages in atherosclerotic lesions serve as effectors of macrophage reprogramming into a hyperinflammatory phenotype.

Keywords: atherosclerosis; inflammation; lipopolysaccharide; macrophages; monocytes

DOI: https://doi.org/10.1161/ATVBAHA.122.318006