PARP-1 Is Critical for Recruitment of Dendritic Cells to the Lung in a Mouse Model of Asthma but Dispensable for Their Differentiation and Function.

Laura C Echeverri Tirado,Hanh H Luu,Hogyoung Kim,Lina M Yassin,Amir A Al-Khami,Mohamed A Ghonim,Dorota Wyczechowska,Jeffrey Wang,José Yélamos,Maria Dulfary Sanchez-Pino,A Hamid Boulares

doi:10.1155/2019/1656484

Abstract

Dendritic cells (DCs) are critical in asthma and many other immune diseases. We previously demonstrated a role for PARP-1 in asthma. Evidence on PARP-1 playing a role in Th2-associated DC function is not clear. In this study, we examined whether PARP-1 is critical for DC differentiation and function using bone marrow progenitors and their migration to the lung in an ovalbumin-based mouse model of asthma. Results show that changes in PARP-1 levels during GM-CSF-induced DC differentiation from bone marrow progenitors were cyclic and appear to be part of an array of changes that included STAT3/STAT5/STAT6/GRAIL/RAD51. Interestingly, PARP-1 gene deletion affected primarily STAT6 and γH2AX. PARP-1 inhibition significantly reduced the migration of DCs to the lungs of ovalbumin-challenged mice, which was associated with a concomitant reduction in lung levels of the adhesion molecule VCAM-1. The requirement of PARP-1 for VCAM-1 expression was confirmed using endothelial and lung smooth muscle cells. PARP-1 expression and activity were also required for VCAM-1 in differentiated DCs. An assessment of CD11b+/CD11c+/MHCIIhigh DCs in spleens and lymph nodes of OVA-sensitized mice revealed that PARP-1 inhibition genetically or by olaparib exerted little to no effect on DC differentiation, percentage of CD80+/CD86+/CD40+-expressing cells, or their capacity to promote proliferation of ovalbumin-primed (OTII) CD4+ T cells. These findings were corroborated using GM-CSF-induced differentiation of DCs from the bone marrow. Surprisingly, the PARP-1−/− DCs exhibited a higher intrinsic capacity to induce OTII CD4+ T cell proliferation in the absence of ovalbumin. Overall, our results show that PARP-1 plays little to no role in DC differentiation and function and that the protective effect of PARP-1 inhibition against asthma is associated with a prevention of DC migration to the lung through a reduction in VCAM-1 expression. Given the current use of PARP inhibitors (e.g., olaparib) in the clinic, the present results may be of interest for the relevant therapies.

Highlights

Asthma is a serious health issue worldwide as it affects more than 300 million adults and children
PARP-1 protein was shown to be absent in human monocytes; expression of the protein emerged after several days upon treatment with GM-CSF and IL-4 or GM-CSF alone [7]
Given that these findings do not necessarily apply to Dendritic cells (DCs) that originate from the bone marrow, we examined the dynamics of PARP-1 protein expression during the process

Summary

Introduction

Asthma is a serious health issue worldwide as it affects more than 300 million adults and children. A common treatment for asthma is a combination of corticosteroids with a β2-agonist; many patients are refractory to these and other established treatments [1]. One of the primary reasons for these side effects is associated with the potent nonselective immunosuppressive properties of the drugs that affect a litany of important physiological processes [2]. Much effort has been invested in identifying drug candidates that may target asthma symptoms that are difficult to treat with existing strategies but without causing major immunosuppression. An examination of the molecular mechanisms that control production of Th2 cytokines and inflammatory factors will undoubtedly increase the likelihood of establishing precise strategies to prevent and/or combat the dire symptoms associated with this disease

Methods

Results

Conclusion