Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation

ABSTRACT

Asthma is a chronic disorder of the airways characterized by cellular infiltration, airway hyper-responsive and airway inflammation. Innate immune cells are the first line of defense against endogenous and exogenous signals in the airways and as such possess a diverse array of pattern recognition receptors. Toll-like receptors are crucial sentinels which when activated, can either promote or ameliorate the inflammatory response in predisposed individuals. The recently discovered triggering receptor expressed on myeloid cells family members are emerging mediators of inflammation. These receptors are believed to modulate inflammatory responses by collaborating with classic PRRs. Endogenous signals like HMGB-1, signaling through the receptor for advanced glycation end products, also promotes inflammation, however, its contribution to inflammation in the airways is not well known. Here, we discuss the role of each receptor in airway inflammation and highlight potential synergistic mechanisms, which contribute to disease pathogenesis in allergic asthma.

KEYWORDS:

• Allergic airway inflammation
• asthma
• DAP12
• HMGB-1
• NF-κB
• RAGE
• TREM
• TLR

Financial & competing interests disclosure

This work was supported by research grants R01 AI075315, R01 HL085680, R01 HL112597, and R01 HL120659 to DK Agrawal from the Office of the Director, National Institutes of Health, and National Heart, Lung and Blood Institute, NIH USA. The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with financial interest or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Asthma is a chronic disorder of the airways affecting approximately 300 million people globally. There is currently no cure for the disease.

• Pattern recognition receptors (PRRs) on innate immune cells enable them to act as the first-line defense against pathogens (viral, bacterial and fungal) that exacerbate the inflammatory response in atopic individuals.

• Several toll-like receptors (TLRs) have been implicated in coordinating the innate immune response and activating adaptive responses driving airway inflammation in asthma. These receptors have also been shown to be amenable targets for therapeutic intervention.

• Triggering receptor expressed on myeloid cells (TREM)-1 and -2 collaborate with TLRs to promote (the former) and dampen (the latter) inflammation.

• Endogenous signals like high-mobility group box-1 can signal through receptor for advanced glycation end products and/or TLRs. Collaborative signaling through both receptors exacerbates inflammation through myeloid differentiation response protein 88-dependent pathways.

• Identification of TREM ligands as well as a better characterization of the mechanism driving collaboration of these PRRs is crucial for the development of targeted therapy for asthma patients.