Inflammatory lung diseases caused by respiratory infections affect more than 5 million people and are the 3rd leading cause of mortality globally. Neutrophils and their derived inflammation are essential for infection resolution. GPCRs are main regulators of neutrophil migration, phagocytic capacity, reactive oxygen species(ROS), and cytokines production. We hypothesize that GPR55 signaling is a potential modulator of neutrophil function & lung injury resolution.

To test our hypothesis, we used an acute lung injury model induced by lipopolysaccharide intratracheal instillation or a vehicle(n=10 per group) using C57BL/6 wildtype(WT) & Gpr55-knockout(KO) mice. Leukocyte counts in blood, bronchoalveolar lavage (BAL), bone marrow (BM), and neutrophil function were determined. Sorted circulating neutrophils from WT & KO mice were characterized by bulk RNA-sequencing(RNAseq).

Lack of GPR55 amplified edema and alveolar neutrophil-ROS production. LPS stimulus increased multipotent myeloid progenitors' numbers in BM in WT but not in Gpr55-KO mice. In blood, neutrophil & monocyte counts were raised in the KO mice compared to the WT group. Lung tissue inflammatory markers (TNFα,IL-1β,IL-6) were reduced in the KO mice. Neutrophil RNAseq data showed that GPR55 deficiency was linked to an upregulation of interferon (IFN)-α/γ response, TNFα signaling, and viral response signaling.

Our data suggest that GPR55 plays a role in neutrophil function, altering the IFN response, which is necessary for immunity response and thereby may aggravate viral infection response. Current investigation using isolated neutrophils and GPR55 agonist/antagonist will clarify the crucial role of GPR55 in neutrophils.