Echeverri Tirado, Laura C.Ghonim, Mohamed A.Wang, JeffreyAl-Khami, Amir A.Wyczechowska, DorotaLuu, Hanh H.Hogyoung, KimSanchez-Pino, Maria DulfaryYélamos López, JoséYassin, Lina M.Boulares, A. Hamid2020-03-022020-03-022019Echeverri Tirado LC, Ghonim MA, Wang J, Al-Khami AA, Wyczechowska D, Luu HH. Et al. 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. Mediators Inflamm. 2019 Apr 24; 2019:1656484. DOI: 10.1155/2019/16564840962-9351http://hdl.handle.net/10230/43757Dendritic 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.application/pdfengCopyright © 2019 Laura C. Echeverri Tirado et al. This is an open access article distributed under the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/ which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PARP-1AsmaPulmons -- Malaltiesinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1155/2019/1656484info:eu-repo/semantics/openAccess