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

Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein‐1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44‐variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44’s ten exons are also alternatively spiced in a cell/tissue‐specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post‐translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside‐out and outside‐in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.