Elsevier

Current Opinion in Immunology

Volume 30, October 2014, Pages 85-90
Current Opinion in Immunology

Homeostatic inflammation in innate immunity

https://doi.org/10.1016/j.coi.2014.08.003Get rights and content

Highlights

  • Pathogen sensors respond not only to pathogens but also to self-derived products.

  • The self-derived products are metabolites such as fatty acids or nucleic acids.

  • The metabolites activate sensors to lead to the homeostatic inflammation.

  • Endolysosome is a crucial intracellular platform for the homeostatic inflammation.

  • Dendritic cells lead to the homeostatic inflammation in a subset-specific way.

Innate immune sensors respond not only to microbial products but also to endogenous metabolites such as nucleic acids (NAs) and lipids. Toll-like receptors (TLRs) deliver a signal from the plasma membrane and also from endolysosomes, where NAs and lipids are catabolized. Interaction of TLRs with metabolites in endolysosomes leads to homeostatic TLR activation. Dendritic cells expressing NA-sensing TLRs are steadily activated by metabolites derived from the host or commensals and produce type I IFNs, thereby provoking various types of inflammatory conditions. Here, we discuss how homeostatic inflammation is induced by innate immune sensors and is involved in maintaining immune homeostasis and causing non-infectious inflammatory diseases.

Introduction

Self-pathogen discrimination continues to be the most important issue in immunology. The innate immune system is thought to have been evolutionally optimized to sense a group of pathogens, but not to react against self. Despite the optimization, Toll-like receptors (TLRs), the founding family of pathogen sensors, still react with self-derived products such as fatty acids, phospholipids, and nucleic acids (NAs), and have been implicated in a variety of autoimmune and non-infectious inflammatory diseases [1]. Receptors in the immune system including B cell receptors, T cell receptors, and NK receptors, all signal from the cell surface, and their signaling is terminated by their internalization. Meanwhile, certain Toll-like receptors (TLRs) are unique in this regard; the endotoxin sensor, TLR4/MD-2, and NA-sensing TLRs such as TLR3/7/8/9 are capable of signaling in the endolysosomes [2], where endogenous TLR ligands like fatty acids, phospholipids, and NAs are present as metabolites (Figure 1). Microbial sensing in the endolysosomes, therefore, takes the risk of reacting with self-derived products that are not yet ‘a danger signal’, but still metabolites.

Homeostatic TLR activation by endogenous metabolites may occur in the healthy state and even has a role in maintaining the integrity of the immune system. For example, antibody (Ab) production and T cell differentiation in the unperturbed state are altered by the lack of TLR signaling [3, 4]. Notably, evidence is accumulating that certain metabolic diseases are influenced by a vicious circle driven by the interaction of pathogen sensors with endogenous metabolites. Pathologic inflammation in non-infectious inflammatory diseases can be understood as an outcome of uncontrolled homeostatic TLR activation. This article focuses on the interaction of TLRs with metabolites in dendritic cells (DCs) and macrophages at the steady and disease state and on the roles of DCs and macrophages in immune homeostasis.

Section snippets

Toll-like receptors respond to self-derived products

Toll-like receptors (TLRs) sense a variety of microbial products. Cell surface TLRs including TLR4/MD-2, TLR1/TLR2, TLR6/TLR2 recognize microbial membrane lipids, whereas TLR3, TLR7, TLR8, and TLR9 are localized to intracellular organelles and recognize microbial NAs [5, 6, 7]. MD-2 has a hydrophobic pocket that accommodates acyl chains of lipopolysaccharides [8]. However, the hydrophobic pocket of MD-2 can also accommodate fatty acids and saturated and unsaturated fatty acids are known to

Innate immune sensing by TLRs in endolysosomes

Type I interferon (IFN) is induced in endolysosomes by TLR4/MD-2 or TLR3/7/8/9 [13, 18]. Considering the interaction between metabolites and TLRs in the endolysosomes, it is important to understand the relationship between TLR-dependent IFN induction and metabolism in endolysosomes (Figure 1). The metabolic state of cells is determined by metabolic sensors including mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). mTOR is recruited to lysosomes and activated by

Nucleic acids (NAs) digestion and innate immune responses

Digestion of metabolites negatively regulates innate immune sensors. An inhibitory role of DNA digestion in NA sensors is shown by the studies on neutral DNase I in the circulation, acidic DNase II in lysosomes, and cytoplasmic DNase III. The loss of function mutation in the DNase I gene predisposes to systemic lupus erythematosis (SLE) in humans and mice [23, 24]. Dnase1−/− mice show SLE-like diseases with anti-nuclear Ab production which leads to the deposition of immune complexes in

Dysregulated NA digestion in the disease state

Excessive stabilization of NAs in the host also leads to activation of NA sensing TLRs, including TLR3, TLR7 and TLR9, which can respond to endogenous NAs. Anti-NA Abs, cationic antimicrobial peptides, or nuclear proteins bind to and stabilize NAs (Figure 1). As a consequence, the accumulated NAs activate TLR7 or TLR9 causing autoimmune diseases such as SLE or psoriasis. One dendritic cell subset, plasmacytoid dendritic cells (pDCs), expresses TLR7 and TLR9 and is featured by the ability to

Homeostatic roles of dendritic cells

Innate immune sensors function mainly in dendritic cells (DCs) or macrophages, which are called as Antigen (Ag) presenting cells. DCs activated by innate sensors are involved in various immune responses not only in microbial infections but also in noninfectious, sterile diseases. Analyses on DC-ablated mice also showed the crucial roles of DCs in maintaining immune homeostasis [30]. It should be noted that DCs are quite heterogeneous and consist of several subsets with subset-specific

Conclusion

Considering that innate immune sensors can be activated by endogenous substances and that those substances are mainly metabolites, the control of their levels is crucial for maintaining immune homeostasis. Food is taken up orally and nutrients are absorbed in the intestine. The metabolites are generated from the ingested ingredients and processed by various tissues including metabolic organs such as liver and heart as well as by lymphoid organs. Surplus metabolites are excreted or reabsorbed in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank Prof. Tatsushi Muta, who unexpectedly and suddenly died of lung embolism in September 2013, for his contribution to the concept ‘homeostatic inflammation’ and for his dedication, as one of the founding members, to the program grant ‘Shizen Enshow’.

References (39)

  • M. Schnare et al.

    Toll-like receptors control activation of adaptive immune responses

    Nat Immunol

    (2001)
  • B. Beutler et al.

    Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large

    Annu Rev Immunol

    (2006)
  • T. Kaisho et al.

    Toll-like receptor function and signaling

    J Allergy Clin Immunol

    (2006)
  • T. Kawai et al.

    The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

    Nat Immunol

    (2010)
  • U. Ohto et al.

    Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa

    Science

    (2007)
  • T. Suganami et al.

    Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages

    Arterioscler Thromb Vasc Biol

    (2007)
  • X.Z. West et al.

    Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands

    Nature

    (2010)
  • C. Settembre et al.

    TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop

    Nat Cell Biol

    (2013)
  • J.C. Kagan et al.

    TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta

    Nat Immunol

    (2008)
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