Complement anaphylatoxins recruit and activate immune cells, whereas the MAC can contribute to both cell lysis and exacerbation of excitotoxic insult to neurons (for review, see Alawieh and Tomlinson, 2016)

Complement anaphylatoxins recruit and activate immune cells, whereas the MAC can contribute to both cell lysis and exacerbation of excitotoxic insult to neurons (for review, see Alawieh and Tomlinson, 2016). weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive, and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials. SIGNIFICANCE STATEMENT Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 d after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI. values 0.05 were considered significant. Student’s test was used to compare two groups and was always used as two-tailed. Pearson correlation coefficients were used to compute correlations. Data are reported as mean SEM unless otherwise specified. Sample size was estimated based on an effect size determined for each outcome measure by pilot and prior studies. G*Power 3 (Universit?t Dsseldorf, Germany) was used to compute sample size using an acceptable power range of 80C90%. Before surgery, animals were LATS1 randomly assigned to treatment organizations and a double-blinded strategy was used in rating and assessment thereafter. Treatment organizations were coded for each animal and was not accessible to cosmetic surgeons and investigators carrying out end result assessment. Behavioral assessments (open field, panic, and Barnes maze) were scored using automated products or video-analysis tools. Details for statistical analyses for each figure are provided here: Number 1 0.0001. All mixtures were compared using Bonferroni test for multiple comparisons. Vehicle versus CR2Crry: 0.0001; Vehicle versus CR2fH: 0.001; Vehicle versus CR2CD59: 0.01. Number 1= 0.5839. ANOVA statistics: = 0.0019. All mixtures were compared using Bonferroni test for multiple comparisons. Vehicle versus CR2Crry: 0.001; Vehicle versus CR2fH: 0.05; Vehicle versus CR2CD59: 0.05. Number 1= 0.004. ANOVA statistics: = 0.9372. Due to a significant BrownCForsythe test, organizations were also analyzed using the KruskalCWallis (KW) test (nonparametric) showing no significant difference (KW = 0.4503, = 0.9297). Number 1= 0.4997. No significant variations were observed. Number 2= 0.3992. ANOVA statistics: = 0.0013. All mixtures were compared using Bonferroni test SB-649868 for multiple comparisons. Vehicle versus SB-649868 CR2Crry: 0.001; Vehicle versus CR2fH: 0.01; Vehicle versus CR2CD59: = 0.45; = 0.4463. ANOVA statistics: = 0.0221. All mixtures were compared using Bonferroni test for multiple comparisons. Vehicle versus CR2Crry: 0.05; Vehicle versus CR-2fH: 0.05; Vehicle versus CR2CD59: = 0.5208; = 0. 2414. ANOVA statistics: = 0.1931. All mixtures were compared using SB-649868 Bonferroni test for multiple comparisons. No significant results detected. Number 2 0.0001. All mixtures were compared using Bonferroni test for multiple comparisons. Vehicle versus CR2Crry: 0.001; Vehicle versus CR2fH: 0.001; CR2Crry or CR2fH versus CR2CD59: 0.05. Number 2= 0.1708. ANOVA statistics: 0.001. All mixtures were compared using Bonferroni test for multiple comparisons. Number 2 0.0001. All mixtures were compared using Bonferroni test for multiple comparisons. Vehicle versus CR2Crry: 0.001; Vehicle versus CR2fH: 0.001; CR2Crry and CR-fH versus CR2CD59: 0.05. Number 2 0.0001. All mixtures were compared using Bonferroni test for multiple comparisons. Vehicle versus CR2Crry: 0.001; Vehicle versus CR2fH: 0.001; CR2Crry and CR-fH versus.