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.
Highlights
Dendritic cells (DCs), macrophages and monocytes are closely related cells derived from the same common myeloid progenitors [1,2]
We investigated the susceptibility of these macrophages to cell death and found that addition of LPS to mFADD-/- bone marrow-derived macrophages (BMDM) but not the wild-type BMDM led to increased cell death (Fig 1B)
Loss of RIP3 alleles completely abolished the LPS-induced necroptosis of mFADD-/- macrophages (S1 Fig)
Summary
Dendritic cells (DCs), macrophages and monocytes are closely related cells derived from the same common myeloid progenitors [1,2]. They share common functions like antigen presentation, participation in T cell development and maintenance of gut immune system homeostasis. Each plays additional distinct roles in the immune system [3,4]. DCs are required for initiation of immunity; DC-less mice exhibit impaired innate immunity and diminished NK and CD8+ T cell responses to infection [5,6]. DCs play an important role in peripheral T cell tolerance as mice with apoptosis-resistant DCs develop autoimmunity [7,8]. Loss of macrophages and monocytes has no overt effects on innate immunity but instead results in reduced Th1 adaptive immunity or defective wound healing [9,10]
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