Spinal cord injury (SCI) often results in permanent loss of motor and sensory function. After SCI, the blood–spinal cord barrier (BSCB) is disrupted, causing the infiltration of neutrophils and macrophages, which secrete several kinds of cytokines, as well as matrix metalloproteinases (MMPs). MMPs are proteases capable of degrading various extracellular matrix (ECM) proteins, as well as many non-matrix substrates. The tissue inhibitor of MMPs (TIMP)-1 is significantly upregulated post-SCI and operates via MMP-dependent and MMP-independent pathways. Through the MMP-dependent pathway, TIMP-1 directly reduces inflammation and destruction of the ECM by binding and blocking the catalytic domains of MMPs. Thus, TIMP-1 helps preserve the BSCB and reduces immune cell infiltration. The MMP-independent pathway involves TIMP-1’s cytokine-like functions, in which it binds specific TIMP surface receptors. Through receptor binding, TIMP-1 can stimulate the proliferation of several types of cells, including keratinocytes, aortic smooth muscle cells, skin epithelial cells, corneal epithelial cells, and astrocytes. TIMP-1 induces astrocyte proliferation, modulates microglia activation, and increases myelination and neurite extension in the central nervous system (CNS). In addition, TIMP-1 also regulates apoptosis and promotes cell survival through direct signaling. This review provides a comprehensive assessment of TIMP-1, specifically regarding its contribution to inflammation, ECM remodeling, and scar formation after SCI.

Spinal cord injury (SCI) triggers a secondary injury cascade characterized by neuroinflammation, reactive gliosis, and neuronal apoptosis. While many pro-inflammatory cytokines contributing to this cascade reach peak upregulation within 24 h, Interleukin-18 (IL-18) exhibits a delayed upregulation profile, typically peaking 7 days post-injury. This review examines the temporal regulation and cell-specific roles contributing to the rise in IL-18 after SCI. Following primary insult, damage-associated molecular patterns prime and activate the NLRP3 inflammasome, which in turn drives latent IL-18 secretion. Cellularly, microglia function as the primary producers of IL-18 via the TLR4/p38-MAPK pathway, while astrocytes serve as the primary responders through IL-18R/p65-NF-κβ signaling. The microglia-astrocyte cross-talk propagates reactive gliosis, drives neuropathic pain, facilitates neuronal loss, and potentially contributes to the formation of the astrocytic border. Targeted therapeutic interventions such as upstream inhibition of NLRP3 inflammasome assembly or direct IL-18 neutralization successfully mitigate neuroinflammation. By either inhibiting NLRP3 inflammasome activation or directly neutralizing IL-18, these treatments shift the microglial toward a protective state, restrict histological damage, and significantly improve functional recovery.