Non‐Resolving Aspects of Acute Inflammation after Spinal Cord Injury (SCI): Indices and Resolution Plateau

Abstract

Inflammatory resolution is an active, highly regulated process already encoded at the onset of inflammation and required to prevent the transition into chronic inflammation associated with spreading of tissue injury and exacerbated scarring. We introduce objective, quantitative measurements [resolution indices (R(i) ) and resolution plateau (R(P) )] to characterize inflammatory resolution and to determine the persistence ("dwell time") of differential leukocyte subpopulations at the lesion site after acute experimental spinal cord injury (SCI). The cell type-specific resolution interval R(i) (time between maximum cell numbers and the point when they are reduced to 50%) ranges from 1.2 days for neutrophils, 1.5 days for T lymphocytes, to 55 days for microglia/macrophages. As the resolution interval neglects exiting cell trafficking in the later period of resolution (49%-0% of lesional cells), we introduced the R(P) , a marker for the persisting, chronified leukocyte subsets, which are likely to participate in late degeneration and non-resolving inflammation. Here, we identify the acute inflammatory response in central nervous system (CNS) lesions as partly non self-limiting. Both extended resolution intervals (reduced leukocyte clearance) and elevated plateaus (permanent lesional cell numbers) provide quantitative measures to characterize residual, sustained inflammation and define cognate timeframes of impaired resolution after acute SCI.