Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Abstract

We have previously reported that prostaglandin D2 Synthase (L‐PGDS) participates in peripheral nervous system (PNS) myelination during development. We now describe the role of L‐PGDS in the resolution of PNS injury, similarly to other members of the prostaglandin synthase family, which are important for Wallerian degeneration (WD) and axonal regeneration. Our analyses show that L‐PGDS expression is modulated after injury in both sciatic nerves and dorsal root ganglia neurons, indicating that it might play a role in the WD process. Accordingly, our data reveals that L‐PGDS regulates macrophages phagocytic activity through a non‐cell autonomous mechanism, allowing myelin debris clearance and favoring axonal regeneration and remyelination. In addition, L‐PGDS also appear to control macrophages accumulation in injured nerves, possibly by regulating the blood–nerve barrier permeability and SOX2 expression levels in Schwann cells. Collectively, our results suggest that L‐PGDS has multiple functions during nerve regeneration and remyelination. Based on the results of this study, we posit that L‐PGDS acts as an anti‐inflammatory agent in the late phases of WD, and cooperates in the resolution of the inflammatory response. Thus, pharmacological activation of the L‐PGDS pathway might prove beneficial in resolving peripheral nerve injury.

Prostaglandin D2 pathway in a transgenic rat model of Alzheimer’s disease: therapeutic potential of timapiprant a DP2 antagonist

“…Sox-2 is also required for proliferation and differentiation of oligodendrocytes during postnatal brain myelination and CNS remyelination [71]. In addition, Sox-2 is a negative regulator of myelination by Schwann cells [20], and its levels are controlled by L-PGDS in PNS injured nerves [22]. We found that Sox-2 expression levels in the hippocampal tissue were quite high (79.4 RPM, Fig.…”

“…In vitro studies also demonstrated that L-PGDS acts as a disaggregase by disassembling Aβ fibrils [30]. In the PNS, L-PGDS contributes to myelination during development [63], and potentially acts as an antiinflammatory agent under conditions of peripheral nerve injury [22]. In the latter studies, L-PGDS modulated the expression of the transcription factor Sox-2, which in the CNS regulates oligodendrocyte proliferation and differentiation [71], and in the PNS is a negative regulator of myelination [20, 22].…”

Biochemical and Structural Characteristics, Gene Regulation, Physiological, Pathological and Clinical Features of Lipocalin-Type Prostaglandin D2 Synthase as a Multifunctional Lipocalin

“…L-PGDS is necessary for macrophage activity and myelin debris clearance in a non-cell autonomous way during the resolution of PNS injury. In late phases of Wallerian degeneration, L-PGDS regulates the bloodnerve barrier permeability and SOX2 expression in Schwann cells, prevents macrophage accumulation, and exerts an antiinflammatory role (Forese et al, 2020). Thus, L-PGDS has a different role during development and after injury in the PNS.…”

Axo‐glial interaction in the injured PNS

“…Macrophages can also be recruited to sensory and sympathetic ganglia after injury in response to increased expression of CCL2 by axotomized neurons, where they participate in the activation of a transcriptional program in the neurons that promotes neurite outgrowth (Cattin & Lloyd, 2016;Kwon et al, 2013Kwon et al, , 2015Niemi, DeFrancesco-Lisowitz, Cregg, Howarth, & Zigmond, 2016;Niemi et al, 2013;Zigmond & Echevarria, 2019). In addition, prostaglandin D2 synthase, potentially via its expression in neurons, has recently been shown to modulate macrophage activity and accumulation after nerve injury (Forese et al, 2020).…”