The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells

Abstract

The role of the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in homeostasis of the immune system is incompletely understood. Here we found that dendritic cells (DCs) constitutively activated the UPR sensor IRE-1α and its target, the transcription factor XBP-1, in the absence of ER stress. Loss of XBP-1 in CD11c+ cells led to defects in phenotype, ER homeostasis and antigen presentation by CD8α+ conventional DCs, yet the closely related CD11b+ DCs were unaffected. Whereas the dysregulated ER in XBP-1-deficient DCs resulted from loss of XBP-1 transcriptional activity, the phenotypic and functional defects resulted from regulated IRE-1α-dependent degradation (RIDD) of mRNAs, including those encoding CD18 integrins and components of the major histocompatibility complex (MHC) class I machinery. Thus, a precisely regulated feedback circuit involving IRE-1α and XBP-1 controls the homeostasis of CD8α+ conventional DCs.

Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

“…Physiologically, XBP1 is necessary for differentiation of B cells, NK cells, and macrophages, although there is no detected basal IRE-1 activity for naive T cells and monocytes from spleen (17). There are only sporadic data on neutrophils (21), and in our study we found that . TNF-a, IL-6, C5a, and MPO were measured using ELISA.…”

“…ER stress is essential for leukocyte generation, and deficiency of C/EBP homologous protein, a target of the PERK signaling pathway, leads to increased total myeloid subpopulations such as neutrophils and F4/80 + macrophages (20). There is no basal IRE1a activity for resting neutrophils (21). However, the neutrophils were displayed as hyperactive in response to inflammatory stress when ER stress was enhanced (22).…”

Cellular and molecular regulation of innate inflammatory responses

“…While Rab11a activity recruits and keeps MHC-I within endosomal recycling compartment (ERC) under steady condition, MyD88-dependent TLR signals drive IKK2-mediated phosphorylation of phagosome-associated SNAP23, orchestrating ERC-phagosome fusion, promoting enrichment of phagosomes with ERC-derived MHC-I, and finally allowing cross-presentation during infection. 139 Transcription factor TFEB, 140 cell stress sensor IRE-1α, [141][142][143] NF-κB-inducing kinase (NIK) 144 and the lectin Siglec-G 145 have been shown to regulate DC cross-presentation in initiating antigen-specific CTL responses via distinct molecular mechanisms. For example, Siglec-G inhibits cross-presentation by CD8α+ DC via impairing the formation of the MHC class I-exogenous antigen peptide complex, contributing to suppression of CTL responses to intracellular bacterial infection with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin and tumors.…”

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…[1][2][3][4] The ER stress response is employed by many types of immune cells to cope with cell stress to avoid apoptosis. [5][6][7][8][9][10][11] The 3 primary regulators of the ER stress response are IRE-1a, PERK, and ATF6. 12 IRE-1a is particularly critical for the function of plasma cells.…”