Interleukin-1 Receptor 1 Deletion in Focal and Diffuse Experimental Traumatic Brain Injury in Mice

Abstract

Important differences in the biology of focal and diffuse traumatic brain injury (TBI) subtypes may result in unique pathophysiological responses to shared molecular mechanisms. Interleukin-1 (IL-1) signaling has been tested as a potential therapeutic target in preclinical models of cerebral contusion and diffuse TBI, and in a phase II clinical trial, but no published studies have examined IL-1 signaling in an impact/acceleration closed head injury (CHI) model. We hypothesized that genetic deletion of IL-1 receptor-1 (IL-1R1 KO) would be beneficial in focal (contusion) and CHI in mice. Wild type and IL-1R1 KO mice were subjected to controlled cortical impact (CCI), or to CHI. CCI produced brain leukocyte infiltration, HMGB1 translocation and release, edema, cell death, and cognitive deficits. CHI induced peak rotational acceleration of 9.7 × 10 ± 8.1 × 10 rad/s, delayed time to righting reflex, and robust Morris water maze deficits without deficits in tests of anxiety, locomotion, sensorimotor function, or depression. CHI produced no discernable acute plasmalemma damage or cell death, blood-brain barrier permeability to IgG, or brain edema and only a modest increase in brain leukocyte infiltration at 72 h. In both models, mature (17 kDa) interleukin-1 beta (IL-1β) was induced by 24 h in CD31+ endothelial cells isolated from injured brain but was not induced in CD11b cells in either model. High mobility group box protein-1 was released from injured brain cells in CCI but not CHI. Surprisingly, cognitive outcome in mice with global deletion of IL-1R1 was improved in CHI, but worse after CCI without affecting lesion size, edema, or infiltration of CD11b/CD45 leukocytes in CCI. IL-1R1 may induce unique biological responses, beneficial or detrimental to cognitive outcome, after TBI depending on the pathoanatomical subtype. Brain endothelium is a hitherto unrecognized source of mature IL-1β in both models.

Contributions of Interleukin-1 Receptor Signaling in Traumatic Brain Injury

“…Knockout mice showed increased performance on some behavioral tests in a CHI and a CCI model compared to their WT counterparts. In a CHI model, constitutive, global elimination of IL-1R1 resulted in a normalization of TBI-induced memory deficits in hidden and visible MWM platform trials, resulting in performance comparable to that of the WT sham mice (Chung et al, 2018). In a Y-Maze study, WT CHI mice had a decrease in alternating decisions compared to their respective sham counterparts, whereas IL-1R1 KO mice performed similarly to WT sham subjects (Chung et al, 2018).…”

“…In a CHI model, constitutive, global elimination of IL-1R1 resulted in a normalization of TBI-induced memory deficits in hidden and visible MWM platform trials, resulting in performance comparable to that of the WT sham mice (Chung et al, 2018). In a Y-Maze study, WT CHI mice had a decrease in alternating decisions compared to their respective sham counterparts, whereas IL-1R1 KO mice performed similarly to WT sham subjects (Chung et al, 2018). No overt effects of IL-1R1 elimination alone were found in any of the behavioral paradigms (Chung et al, 2018), providing evidence that inflammatory signaling mediated by IL-1R1 is involved in spatial and working memory deficits following CHI.…”

“…In a Y-Maze study, WT CHI mice had a decrease in alternating decisions compared to their respective sham counterparts, whereas IL-1R1 KO mice performed similarly to WT sham subjects (Chung et al, 2018). No overt effects of IL-1R1 elimination alone were found in any of the behavioral paradigms (Chung et al, 2018), providing evidence that inflammatory signaling mediated by IL-1R1 is involved in spatial and working memory deficits following CHI. It should be noted that due to the constitutive nature of IL-1R1 elimination in these subjects the temporal requirements for IL-1R1-mediated signaling in driving these effects are currently unknown.…”

“…The role of IL-1R1 has been investigated utilizing genetic knockout models of the receptor. Early experiments involved mice with a global IL-1R1 knockout (Chung et al, 2018). Knockout mice showed increased performance on some behavioral tests in a CHI and a CCI model compared to their WT counterparts.…”

Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

“…Pro-inflammatory responses at the acute phase after traumatic brain injury (TBI) are characterized by elevated pro-inflammatory cytokines produced by activated microglia, astrocytes, and infiltrated peripheral inflammatory cells, which cause blood-brain barrier (BBB) permeability and neurotoxicity, thereby worsening outcomes [1][2][3]. Annexin A2 (AnxA2) is a 36 KD multi-compartmental protein that exists as a monomer or a heterotetrameric complex with the S100A10 (P11).…”