Journal
ADVANCED SCIENCE
Volume 9, Issue 22, Pages -Publisher
WILEY
DOI: 10.1002/advs.202103701
Keywords
Cyclic GMP-AMP synthase; STING signaling; interleukin-6; malaria; proinflammatory monocytes
Categories
Funding
- National Cancer Institute, NIH [R01CA101795, U54CA210181]
- Houston Methodist Research Institute
- University of Southern California
- National Science Foundation of China [82171741, 81801579]
- Science and Technology Planning Project of Guangzhou [201904010064]
- Guangdong Basic and Applied Basic Research Foundation [2019B1515120033, 2021A1515012140]
- Zhujiang Youth Scholar funding
- Southern Medical University
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Instites of Health (NIH), USA
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The cGAS-STING-MyD88-p38 axis plays a detrimental role in regulating anti-malaria immunity by inducing late IL-6 production and proinflammatory monocyte expansion. Inhibition of this signaling pathway or depletion of proinflammatory monocytes improves mouse survival during lethal malaria infections.
Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) play critical roles in the innate immunity against infectious diseases and are required to link pathogen DNA sensing to immune responses. However, the mechanisms by which cGAS-STING-induced cytokines suppress the adaptive immune response against malaria infections remain poorly understood. Here, cGAS-STING signaling is identified to play a detrimental role in regulating anti-malaria immunity. cGAS or STING deficiency in mice markedly prolongs mouse survival during lethal malaria Plasmodium yoelii nigeriensis N67C infections by reducing late interleukin (IL)-6 production. Mechanistically, cGAS/STING recruits myeloid differentiation factor 88 (MyD88) and specifically induces the p38-dependent signaling pathway for late IL-6 production, which, in turn, expands CD11b(+)Ly6C(hi) proinflammatory monocytes to inhibit immunity. Moreover, the blockage or ablation of the cGAS-STING-MyD88-p38-IL-6 signaling axis or the depletion of CD11b(+)Ly6C(hi) proinflammatory monocytes provides mice a significant survival benefit during N67C and other lethal malaria-strain infections. Taken together, these findings identify a previously unrecognized detrimental role of cGAS-STING-MyD88-p38 axis in infectious diseases through triggering the late IL-6 production and proinflammatory monocyte expansion and provide insight into how targeting the DNA sensing pathway, dysregulated cytokines, and proinflammatory monocytes enhances immunity against infection.
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