Deletion of FADD in Macrophages and Granulocytes Results in RIP3- and MyD88-Dependent Systemic Inflammation

Abstract

Myeloid cells, which include monocytes, macrophages, and granulocytes, are important innate immune cells, but the mechanism and downstream effect of their cell death on the immune system is not completely clear. Necroptosis is an alternate form of cell death that can be triggered when death receptor-mediated apoptosis is blocked, for example, in stimulated Fas-associated Death Domain (FADD) deficient cells. We report here that mice deficient for FADD in myeloid cells (mFADD-/-) exhibit systemic inflammation with elevated inflammatory cytokines and increased levels of myeloid and B cell populations while their dendritic and T cell numbers are normal. These phenotypes were abolished when RIP3 deficiency was introduced, suggesting that systemic inflammation is caused by RIP3-dependent necroptotic and/or inflammatory activity. We further found that loss of MyD88 can rescue the systemic inflammation observed in these mice. These phenotypes are surprisingly similar to that of dendritic cell (DC)-specific FADD deficient mice with the exception that DC numbers are normal in mFADD-/- mice. Together these data support the notion that innate immune cells are constantly being stimulated through the MyD88-dependent pathway and aberrations in their cell death machinery can result in systemic effects on the immune system.

Necroptosis: Mechanisms and Relevance to Disease

“…Moreover, the deletion of Fadd from the myeloid cell compartment provokes systemic inflammation that can be abolished by the concomitant absence of Ripk3 or myeloid differentiation primary response 88 ( Myd88 ) (69), whereas Casp8 −/− or Fadd −/− T cells exhibit considerable activation and proliferation defects, which can be partially rescued by the RIPK1 inhibitor necrostatin-1 (Nec-1) or by the concomitant absence of Ripk3 (45, 70–72). Thus, the regulation of lethal signal transduction cascades emanating from TNFR1 plays a critical role not only in embryonic development but also in the maintenance of epithelial and immunological homeostasis.…”

The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

“…Mice with a targeted Fadd deletion in neutrophil and monocyte/macrophage populations have chronic inflammation associated with elevated production of proinflammatory cytokines and increased populations of macrophages, neutrophils and B cells 92 . Global deletion of Myd88 has been found to rescue these phenotypes, indicating that the inflammation caused by the loss of FADD is attributable to MyD88 signalling, rather than defects in cell death 92 .…”

The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

“…These phenotypes are attributed to the downstream effects of depletion of CD103 + dendritic cells within gut-associated lymphoid tissues due to the loss of FADD [125]. This same group also assessed the impact of myeloid cell-specific FADD-deficiency, and similar to CD11c cre FADD flox/flox mice, LysM cre/cre FADD flox/flox mice, which have nearly complete deletion of FADD in neutrophil and monocyte/macrophage populations, suffer from systemic inflammation along with pro-inflammatory cytokines, including MCP-1, and increased macrophage, neutrophil and B cell populations [126]. However, despite the systemic inflammation observed in CD11c cre FADD flox/flox and LysM cre/cre FADD flox/flox mice, kidney pathology was not assessed.…”

“…Disease in CD11c cre FADD flox/flox mice is prevented by global, but not dendritic cell-specific, deletion of MyD88 as well as oral antibiotic treatment [125]. Further global deletion of MyD88 rescues these phenotypes, indicating that the inflammation observed due to the loss of FADD is driven by MyD88 signaling and not a defect in death [126]. Since kidney pathology was not examined in mice with dendritic cell- or myeloid-cell specific FADD deletion, assessment of kidney damage in the context of cell-specific FADD deficiency merits investigation.…”

“…Deletion of either RIPK1 or RIPK3 can rescue the embryonic lethality that occurs with global knockout of either FADD or caspase-8, but not FLIP [180, 188, 189], and deletion of RIPK3 in CD11c cre FADD flox/flox and LysM cre/cre FADD flox/flox mice also rescues the phenotypes associated with phagocyte-specific FADD deficiency [125, 126]. Similar to CD11c cre FADD flox/flox and LysM cre/cre FADD flox/flox mice, deletion of RIPK3 prevents disease symptoms in LysM cre/cre Casp8 flox/flox mice resulting from caspase-8 deficiency in myeloid cells [149].…”