The Role of Osteopontin in Microglia Biology: Current Concepts and Future Perspectives

Abstract

The innate immune landscape of the central nervous system (CNS), including the brain and the retina, consists of different myeloid cell populations with distinct tasks to fulfill. Whereas the CNS borders harbor extraparenchymal CNS-associated macrophages whose main duty is to build up a defense against invading pathogens and other damaging factors from the periphery, the resident immune cells of the CNS parenchyma and the retina, microglia, are highly dynamic cells with a plethora of functions during homeostasis and disease. Therefore, microglia are constantly sensing their environment and closely interacting with surrounding cells, which is in part mediated by soluble factors. One of these factors is Osteopontin (OPN), a multifunctional protein that is produced by different cell types in the CNS, including microglia, and is upregulated in neurodegenerative and neuroinflammatory conditions. In this review, we discuss the current literature about the interaction between microglia and OPN in homeostasis and several disease entities, including multiple sclerosis (MS), Alzheimer’s and cerebrovascular diseases (AD, CVD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD) and diabetic retinopathy (DR), in the context of the molecular pathways involved in OPN signaling shaping the function of microglia. As nearly all CNS diseases are characterized by pathological alterations in microglial cells, accompanied by the disturbance of the homeostatic microglia phenotype, the emergence of disease-associated microglia (DAM) states and their interplay with factors shaping the DAM-signature, such as OPN, is of great interest for therapeutical interventions in the future.

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

“…Together, MERTK and GAS6 promote homeostasis and neuronal survival and they are disrupted in several nervous system disorders 57 . On the other hand, microglial osteopontin (SPP1), promotes remyelination in multiple sclerosis and is neuroprotective near infarcts in stroke but in Alzheimer's disease it is part of the "disease associated microglia" signature 58 . The role of these signaling molecules in depression, if any, are yet to be determined.…”

Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

“…Indeed, OPN/SPP1 is a potent sensor in the central nervous system responding to different types of acute or cumulative damage in cellular/tissue state or physiology that disrupts homeostasis, for example, in neurodegenerative disorders in which inflammation is a prominent component 14 . In multiple sclerosis and Alzheimer's disease (AD) models and humans, OPN/SPP1 is elevated in the plasma and CSF in those with advanced disease 15‐19 . It is also a member of a highly expressed gene signature of so‐called neurodegenerative microglia that includes ApoE 10‐12 .…”

Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection

“…In the microglia clusters 1-4 and 6, transcripts for immediate early response 3 (IER3), a feedback inhibitor of NF-κB in the inflammatory response ( 95 ), were increased, as was the mRNA for receptor activity-modifying protein 1 (RAMP1), a component of the calcitonin gene-related peptide receptor complex, which has microglia-activating activity ( 96 ). Also increased was the sodium bicarbonate cotransporter 3 (SLC4A7), critical for phagosome acidification ( 97 ), and SPP1 (especially prominent in cluster 3), a pleiotropic cytokine with numerous links to CNS diseases ( 98 ). There was no such change in the expression of these genes in macrophage cluster 5.…”