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Review
. 2020 Mar 12;9(3):695.
doi: 10.3390/cells9030695.

ER Stress Responses: An Emerging Modulator for Innate Immunity

Giusy Di Conza  1   2 , Ping-Chih Ho  1   2
Affiliations
Review

ER Stress Responses: An Emerging Modulator for Innate Immunity

Giusy Di Conza et al. Cells. .

Abstract

The endoplasmic reticulum (ER) is a critical organelle, storing the majority of calcium and governing protein translation. Thus, it is crucial to keep the homeostasis in all ER components and machineries. The ER stress sensor pathways, including IRE1/sXBP1, PERK/EIf2 and ATF6, orchestrate the major regulatory circuits to ensure ER homeostasis. The embryonic or postnatal lethality that occurs upon genetic depletion of these sensors reveals the essential role of the ER stress pathway in cell biology. In contrast, the impairment or excessive activation of ER stress has been reported to cause or aggravate several diseases such as atherosclerosis, diabetes, NAFDL/NASH, obesity and cancer. Being part of innate immunity, myeloid cells are the first immune cells entering the inflammation site. Upon entry into a metabolically stressed disease environment, activation of ER stress occurs within the myeloid compartment, leading to the modulation of their phenotype and functions. In this review, we discuss causes and consequences of ER stress activation in the myeloid compartment with a special focus on the crosstalk between ER, innate signaling and metabolic environments.

Keywords: ER stress; chronic diseases; infection; innate immunity.

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Conflict of interest statement

P.-C.H. is a member of scientific advisory board for Elixiron Immunotherapeutics and receiving research support from Idorsia and Roche.

Figures

Figure 1
Figure 1
Engagement of ER stress responses in macrophages. Macrophage activation occurs through Toll-like receptors (TLRs) upon binding with DAMPs (Damage-associated molecular patterns) and PAMPs (Pathogen-associated molecular patterns). IRE1, as downstream target of TLRs, induces XBP1 splicing and inflammasome activation therefore promoting generation of pro-inflammatory cytokines. This function of IRE1 is essential to keep homeostasis and to successfully resolve acute infections. On the other hand, many chronic diseases are characterized by a metabolically altered microenvironment, which promotes unfolded protein response (UPR) activation. In addition to that, activated macrophages uptake lipids from the extracellular space, leading to change in the lipid composition of the ER membrane. UPR and lipid accumulation trigger an excessive IRE1/PERK-mediated ER stress response that results in chronic release of pro-inflammatory mediators and induction of cell death that contributes to the progression of disease.
Figure 2
Figure 2
The multifaceted roles of ER stress responses in myeloid cells. ER stress mediators play an important role in modulating development and function of innate immune cells. Immature dendritic cells (in light blue) require IRE1/XBP1 activation in order to differentiate in mature DCs. Mature DCs, upon encountering DAMPs and PAMPs activate PERK/CHOP pathway to accomplish a full activation and the release of IL-23. In macrophages IRE1/XBP1 promotes activation of proinflammatory IL-6 and TNF. However, in disease context, excessive activation of ER stress upon lipid accumulation lead to the formation of foam cells, cell death and impaired resolutive response. In neutrophils, activation of ER stress is associated with increased cell death during development and upon tissue damage. In the context of hyperinsulinemia, mast cells accumulate lipid bodies that cause ER stress response IRE1/XBP1, which results in inhibition of degranulation. Eosinophil precursor (EoP) constitutively activate XBP1 in order to give rise to mature eosinophils.
See this image and copyright information in PMC

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