Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Abstract

Throughout the body, the extracellular matrix (ECM) provides structure and organization to tissues and also helps regulate cell migration and intercellular communication. In the injured spinal cord (or brain), changes in the composition and structure of the ECM undoubtedly contribute to regeneration failure. Less appreciated is how the native and injured ECM influences intraspinal inflammation and, conversely, how neuroinflammation affects the synthesis and deposition of ECM after CNS injury. In all tissues, inflammation can be initiated and propagated by ECM disruption. Molecules of ECM newly liberated by injury or inflammation include hyaluronan fragments, tenascins, and sulfated proteoglycans. These act as “damage-associated molecular patterns” or “alarmins”, i.e., endogenous proteins that trigger and subsequently amplify inflammation. Activated inflammatory cells, in turn, further damage the ECM by releasing degradative enzymes including matrix metalloproteinases (MMPs). After spinal cord injury (SCI), destabilization or alteration of the structural and chemical composition of the ECM affects migration, communication, and survival of all cells – neural and non-neural – that are critical for spinal cord repair. By stabilizing ECM structure or modifying their ability to trigger the degradative effects of inflammation, it may be possible to create an environment that is more conducive to tissue repair and axon plasticity after SCI.

Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model

“…Within the first 24 h after injury, neutrophils are among the first immigrating cells occupying the injury site followed by monocytes and macrophages [35,36]. Membrane spanning Toll-like receptors (TLRs) and the cytoplasmic sensors Nod-like receptors (NLRs), which recognize pathogens and initiate innate immune responses to protect the host also sense damaged tissue/cells and released stressor ligands, are functionally implicated in the propagation of SCI-related inflammatory cascade [37][38][39]. These receptors are typically expressed by a variety of spinal cord cells under regular and pathological conditions [40].…”

Materials and technologies for soft implantable neuroprostheses

“…The ECM consists of fibrous proteins, proteoglycans and glycosaminoglycans, such as laminin and hyaluronan. In the CNS, these elements form a dense mesh [39][40][41][42] with a striking scarcity of collagen, which is the dominant ECM component elsewhere in the body 43 . In the adult human CNS, the total volume fraction of the ECM is about 20% 44 .…”

Inhibition of p21-Activated Kinase 1 by IPA-3 Promotes Locomotor Recovery After Spinal Cord Injury in Mice

“…Because PAK1 is an important upstream regulator of a variety of MMPs, inhibition of PAK1 by IPA-3 may exert neuroprotection via inhibition of certain types of MMPs. Furthermore, MMPs play an important role in inflammatory response, 31,32 and they are activated in neurodegenerative diseases 33,34 and trauma. 35,36 Neurons, astrocytes, microglia, and invaded neutrophils express MMP-2 and MMP-9.…”