MyD88 as a therapeutic target for inflammatory lung diseases

ABSTRACT

Introduction: Myeloid differentiation primary response protein 88 (MyD88) is a critical adaptor protein involved in Toll-like and IL-1 receptor family signaling controlling innate immune responses and inflammation. Genetic deletion of MyD88 function results in profound suppression of inflammation and reduced resistance of the host to pathogens indicating non-redundant roles of MyD88. The TIR domain is critical for MyD88 dimerization and signaling for TLR and IL-1R family receptor.

Areas covered: Emerging evidence suggests that chemical disruption of the TIR domain attenuates cell activation and inhibits in vivo MyD88-dependent inflammation. We review the development of MyD88 dimerization disruptors as a novel therapeutic approach of respiratory diseases with a focus on COPD.

Expert opinion: There is a proof of concept that therapeutic targeting of MyD88 is feasible and first preclinical data are highly promising. This opens a great opportunity to treat exacerbations of COPD and other chronic respiratory diseases. However, extensive preclinical investigations and risk analyses are required with carefully evaluation of reduced host resistance and opportunistic infections.

KEYWORDS:

• COPD
• Myd88 inhibitor
• inflammation
• iinterleukin
• toll-like receptor

Article highlights

• TLR and IL-R activation induces dimerization of the adaptor protein MyD88 leading to kinase activation.

• The molecular structure analysis allowed the development of inhibitors disrupting MyD88 dimerization

• Novel pharmacological MyD88 disruptors attenuate TLR and IL-1R activation and inflammation in vivo

• MyD88 disruptors might be used in respiratory inflammation such as COPD and related diseases

• However, complete disruption of MyD88 reduces host resistance with a high risk of infection

• Prior clinical use more pharmacological and toxicological research on MyD88 inhibitors is required

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

European Union FEDER BIO-TARGET Region Centre Val de Loire (N° 2016-00110366)