Cyclooxygenase-Derived Prostaglandin E2 Drives IL-1–Independent Mycobacterium bovis Bacille Calmette-Guérin–Triggered Skin Dendritic Cell Migration to Draining Lymph Node

Abstract

Inoculation of Mycobacterium bovis Bacille Calmette-Guérin (BCG) in the skin mobilizes local dendritic cells (DC) to the draining lymph node (dLN) in a process that remains incompletely understood. In this study, a mouse model of BCG skin infection was used to investigate mechanisms of skin DC migration to dLNs. We found enhanced transcription of cyclooxygenase (COX)-2 and production of COX-derived PGE 2 early after BCG infection in skin. Animals treated with antagonists for COX or the PGE 2 receptors EP2 and EP4 displayed a marked reduction in the entry of skin DCs and BCG to dLNs, uncovering an important contribution of COX-derived PGE 2 in this migration process. In addition, live BCG bacilli were needed to invoke DC migration through this COX-PGE 2 pathway. Having previously shown that IL-1R partially regulates BCG-induced relocation of skin DCs to dLNs, we investigated whether PGE 2 release was under control of IL-1. Interestingly, IL-1R ligands IL-1α/β were not required for early transcription of COX-2 or production of PGE 2 in BCG-infected skin, suggesting that the DC migration-promoting role of PGE 2 is independent of IL-1α/β in our model. In DC adoptive transfer experiments, EP2/EP4, but not IL-1R, was needed on the moving DCs for full-fledged migration, supporting different modes of action for PGE 2 and IL-1α/β. In summary, our data highlight an important role for PGE 2 in guiding DCs to dLNs in an IL-1–independent manner.

Long Way of Evaluating Niacin for Atherosclerosis Treatment

“…Some researchers were concerned that suppression of PGD2 could potentially impact the antiinflammatory action of nicotinic acid, such as PGD2induced inhibition of antigen-presenting Dendritic Cells (DC) activation in inflammation (VanHorn et al, 2012). A study involving mouse models has demonstrated that shortterm administration of niacin can suppress the retention of DC in lymph nodes and that this effect is not abolished by naproxen-induced suppression of prostaglandin generation (Krmeska et al, 2022). Furthermore, another in vitro experiment in human monocytes has clearly shown that the anti-inflammatory action of niacin was not affected by PGD2 inhibition, as evidenced by the measurements of 352 TNF-α, MCP1 and interleukin 6 (Giri et al, 2019).…”

BCG infection dose guides dendritic cell migration and T cell priming in the draining lymph node

“…In mouse models, BCG dose can easily range from 5 × 10 5 to 10 7 colony‐forming units (CFUs) independent of the route of administration. For instance, in our research we have routinely worked with 1–2 × 10 6 CFUs of BCG injected in the footpad skin, ear dermis, or i.v 2,14–17 …”

“…For instance, in our research we have routinely worked with 1-2 × 10 6 CFUs of BCG injected in the footpad skin, ear dermis, or i.v. 2,[14][15][16][17] Prior work on the implications of BCG dose on immune responses has mostly focused on protection against M. tuberculosis challenge, while the more immediate, immunological reactions unleashed by escalating BCG dose in vivo are largely uncharacterized. In the current study, we used a mouse model of BCG skin infection to investigate the early events that unfold in the LN draining the BCG injection site in the skin.…”

Glucose metabolism and its role in the maturation and migration of human CD1c+ dendritic cells following exposure to BCG

“…The murine counterpart of human CD1c + mDCs - CD11b + cDCs - initiate Th1 T cell immunity during pulmonary Mtb infection ( Lai et al., 2018 ). Moreover, migratory epidermal CD11b hi cDCs transport BCG from the skin to draining LN to prime CD4 + T cells following BCG inoculation ( Bollampalli et al., 2015 ; Krmeska et al., 2022 ). Human blood-derived CD1c + mDCs are susceptible to infection with BCG, up-regulating CD40, CCR7, HLA-DR, CD86 and other maturation markers, as well as producing TNF-α and IL-6 ( Lozza et al., 2014 ).…”