early cellular responses to TNF did not rely on TRIF
BM from CD45.2 B6 or Trif−/− donors
these findings highlighted the importance of a balanced immune response, because the low levels of cytokine production observed in Trif−/− mice (Fig. 3, C to E) were sufficient to promote immune cell recruitment and/or proliferation in the spleen (Fig. 4, B to D) without driving massive cell death (Fig. 3, F to K) and animal lethality
the number of macrophages and neutrophils was markedly decreased in B6 spleens and increased in the spleens of Trif−/− mice in response to TNF
immune cell recruitment to and/or proliferation in the spleen in the absence of overwhelming cell death
RPMs containing phagocytosed erythrocytes
phagocytosis of damaged and senescent erythrocytes and produce type I IFNs
splenic red pulp macrophages (RPMs) and erythrocytes
single-cell RNA sequencing (SCS) on the spleens of mice 4 hours after injection with TNF.
TLR3 and TLR4 may sequester stores of TRIF, dampening the response to TNF.
spleen TNF and IFN-β levels were significantly attenuated in Trif−/−, Cd14−/−, and Trif−/−Cd14−/− mice
TNF-induced splenic cell death was markedly decreased in Trif−/− mice
increased leukocyte (mainly neutrophil) infiltration that was absent in the TNF-treated TRIF-deficient animals
a potential background change in mice with TRIF deficiency.
lytic cell death and liver damage
microbial leakage from the gut and the release of endogenous damage signals could be responsible for driving our TRIF-dependent phenotype in response to TNF.
These findings support a model in which, in the absence of TAK1 activity, TRIF-mediated activation downstream of TNF-R1 leads to the formation of a TRIF-dependent prodeath complex (prodeath TRIFosome) containing FADD, RIPK1, and caspase-8, which amplifies cell death via enhanced activation of GSDMD and executioner caspases (Fig. 1, G and H).
the TRIFosome, a pro-death complex formed downstream of the TLR4-adaptor TRIF, in TNF-induced sepsis in mice.
antioxidants inhib
related samples Wilcoxon signed rank test)