Homeostatic inflammation in innate immunity
Graphical abstract
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’.
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