From the low-density lipoprotein receptor-related protein 1 to neuropathic pain: a potentially novel target

Abstract

This review describes the roles of the low-density lipoprotein receptor-related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood-brain barrier and the blood-nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal-regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.

Keywords: ERK; Inflammation; JNK; LRP-1; NFκB; Neurodegeneration; Neuropathic pain; Neuropathies; Neuroregeneration.

Figure 1.

Proinflammatory pathways regulated by LRP-1: The interaction between LRP-1 and ApoE represses the formation of IRAK1–TRAF6 complex and therefore the NFκB-mediated pathway. Shedding of LRP-1 releases the extracellular soluble LRP-1 (sLRP-1) and the intracellular domain (ICDLRP-1). ICDLRP-1 can translocate to the nucleus and arrest IRF-3, inhibiting the TRIF-mediated pathway. Likewise, cytoplasmic ICDLRP-1 can arrest p-JNK, inhibit its translocation to the nucleus, and therefore suppress this MAPK pathway. Images from https://smart.servier.com/, under the Creative Common Attribution 3.0 Unported Licence. ApoE, apolipoprotein E; CCL2/3/4, chemokine (C-C motif) ligand 2/3/4; ECM, extracellular matrix; ICM, intracellular matrix; IFN-β, interferon β, IL-1β, interleukin 1β; IL-6, interleukin 6; IRAK1, interleukin-1 receptor–associated kinase 1; IRF-3, interferon regulatory factor 3; JNK, c-Jun N-terminal kinase; LDL, low-density lipoprotein; LRP-1, low-density lipoprotein receptor-related protein 1; miR-155, microRNA 155; MyD88, myeloid differentiation primary response gene 88; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNFα, tumor necrosis factor α; TRAF6, TNF receptor–associated factor 6; TRIF, TIR domain–containing adapter-inducing interferon β.

Figure 2.

LRP-1 modulates glial cells upon injury: In the CNS: The interaction between LRP-1 and ApoE can induce the polarization of microglia M1 (proinflammatory) into M2 (anti-inflammatory) and reduce the reactive astrogliosis. LRP-1 binding with ApoE can prevent BBB breakdown, whereas LRP-1 and tPA promotes it. LRP-1 is involved in the maturation of oligodendrocytes, although the process is yet unclear. In the PNS: The interaction between LRP-1 and ApoE can induce the polarization of macrophages M1 (proinflammatory) into M2 (anti-inflammatory). LRP-1 interaction with tPA promotes BNB breakdown. LRP-1 in Schwann cells is involved in nerve sprouting and abnormal regeneration. This might be deleterious for the axons. LRP-1 interaction with ApoE or tPA through NMDA-R promotes the migration of Schwann cells to the injury site. Binding of LRP-1 and tPA promotes the Schwann cell repairing phenotype to promote regeneration. Images from https://smart.servier.com/, under the Creative Common Attribution 3.0 Unported Licence. ApoE, apolipoprotein E; BBB, blood–brain barrier; BNB, blood–nerve barrier; CNS, central nervous system; LDL, low-density lipoprotein; LRP-1, LDL receptor–related protein 1; NMDA-R, N-methyl-d-aspartate receptor; OPCs, oligodendrocyte progenitor cells; PNS, peripheral nervous system; tPA, tissue-type plasminogen activator.

Figure 3.

LRP-1 modulates neurodegeneration and neuroregeneration. The inflammatory mediator TNFα can bind to TNFR and activates TRADD–FADD interaction to induce a cascade of proteases (caspase 8 and 10) that lead to apoptosis. TNFR can also activate TRAF1–2 complex to activate NFκB that will increase the expression of TNFα and IL-1β, creating a proinflammatory loop. The inflammatory mediator IL-1β can bind to IL-1R. Activation of TNFR and IL-1B can activate JNK/p38 MAPK pathways, resulting in apoptosis. LRP-1 can indirectly reduce apoptosis by attenuating inflammation. LRP-1 can also arrest JNK in the cytoplasm and inhibit the expression of proapoptotic genes. Coupling of LRP-1 and Trk and transactivation through SDK activates the ERK (1/2)-Akt signaling pathway. This results in cell survival, neurite growth, and axonal regeneration. Images from https://smart.servier.com/, under the Creative Common Attribution 3.0 Unported Licence. ECM, extracellular matrix; ERK1/2, extracellular signal–regulated kinases 1/2; FADD, Fas-associated death domain; ICM, intracellular matrix; IL-1β, interleukin 1β; IL-1R, interleukin-1 receptor; IL-6, interleukin-6; JNK, c-Jun N-terminal kinase; LDL, low-density lipoprotein; LRP-1, LDL receptor–related protein 1; NGF, neurotrophic growth factor; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; SFK, Src family kinase; TNFα, tumor necrosis factor α; TNFR, TNF-α receptor; TRADD, TNFR-associated domain protein; TRAF1/2, TNF receptor–associated factor 1/2; Trk, tyrosine kinase.