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

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.

PARP inhibition and immune modulation: scientific rationale and perspectives for the treatment of gynecologic cancers

“…PARP1 has been shown in several contexts to be important for the recruitment of dendritic cells to sites of inflammation, possibly through regulation of VCAM-1 expression. 46 – 48 In contrast, in a murine model of PARP1 deficiency and selective PARP2 deficiency in T-cells, intratumoral infiltration by CD11b dendritic cells was higher compared with settings of PARP1 deficiency, PARP2 deficiency, or control. 25 Whether PARP is critical to the function of dendritic cells remains unclear, as some studies suggest that PARPi impaired the maturation and antigen presenting function of DCs, 47 , 48 while other studies did not.…”

“… 25 Whether PARP is critical to the function of dendritic cells remains unclear, as some studies suggest that PARPi impaired the maturation and antigen presenting function of DCs, 47 , 48 while other studies did not. 46 …”

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

“…In addition, they also upregulate cell surface receptors, including CD80, CD86, and CD40, which interact with co-receptors on the T cells surface (CD40L and CD28), in order to induce proper T cell activation [64,65]. While the role of PARP-1 in the recruitment of DC to tissues in different pathological situations seems to be well-established, its role in the differentiation and function of these cells is less clear [66][67][68][69]. On the other hand, the function of PARP-2 in DC remains unexplored (Figure 3).…”

“…Dendritic cell function Impaired recruitment [66][67][68][69] Natural killer (NK) cell function Impaired recruitment [72] One of the most successful strategies for reinstating an existing anti-cancer T cell immune response is the use of blocking antibodies against cell surface inhibitory co-receptors like cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PD-1), which block the engagement of PD-1 or CTLA4 with their ligand (PD-L1 and PD-L2 for PD1; CD80/CD86 for CTLA4), thus avoiding the initiation of signaling pathways leading to the suppression of T cell activation. Of note, PARP inhibitors upregulate the expression of PD-L1 in cancer cells and enhance cancer-associated immunosuppression (Figure 4).…”

Mimicking Antigen-Driven Asthma in Rodent Models—How Close Can We Get?

“…The transgenic technology allowed the generation of mice with characteristics of chronic asthma and airway remodeling (102,103). Furthermore, transgenic models allowed the identification of an important migration factor of DCs to the lung (104) and the role of IL-33 receptor suppressor of tumorigenicity 2 (ST2) in development of chronic asthma in mice by regulating ILC2s, mast cells, IL9 and IL-13 in the lungs (105). In addition, recent gene modification in mice allowed to identify for example the role of the potassium channels Kca3.1 in airway remodeling (106), and the regulatory role of semaphorin 3E (Sema3E) in inflammatory and remodeling responses in chronic asthma (107).…”