The orphan receptor GPR84 drives inflammation in Buruli ulcer development

Area of Science:

• Immunology
• Infectious Diseases
• Dermatology

Background:

• Inflammatory responses significantly influence infectious disease progression and outcomes.
• Buruli ulcer, caused by Mycobacterium ulcerans, presents complex immune responses, including immunosuppression and inflammation.
• Spontaneous healing of Buruli ulcer is rare but observed in human cases.

Purpose of the Study:

• To investigate the role of the orphan receptor GPR84 in Buruli ulcer pathogenesis.
• To explore GPR84 as a potential therapeutic target for Buruli ulcer.
• To identify GPR84 expression as a biomarker for Buruli ulcer lesion activity.

Main Methods:

• Genetic inactivation of GPR84 in a mouse model of Buruli ulcer.
• Analysis of GPR84 expression following M. ulcerans infection.
• Pharmacological inhibition of GPR84 using PBI-4050 in combination with antibiotics.
• Assessment of lesion healing, inflammatory cytokine release, and tissue repair.

Main Results:

• Genetic inactivation of GPR84 led to spontaneous healing of ulcerative lesions.
• M. ulcerans infection upregulated Gpr84 expression via Toll-like receptor 2 engagement.
• GPR84 promoted a self-amplifying inflammatory loop, sustaining cytokine release.
• GPR84 inhibition accelerated tissue repair and attenuated inflammation in infected mice.

Conclusions:

• GPR84 plays a critical role in sustaining inflammation during Buruli ulcer.
• Targeting GPR84 offers a promising host-directed therapeutic strategy for Buruli ulcer.
• GPR84 expression may serve as a biomarker for Buruli ulcer lesion activity.