AMPK induces regulatory innate lymphoid cells after traumatic brain injury
Babak Baban, … , Kumar Vaibhav, Krishnan M. Dhandapani
Babak Baban, … , Kumar Vaibhav, Krishnan M. Dhandapani
Published January 11, 2021
Citation Information: JCI Insight. 2021;6(1):e126766. https://doi.org/10.1172/jci.insight.126766.
View: Text | PDF
Research Article Immunology Neuroscience

AMPK induces regulatory innate lymphoid cells after traumatic brain injury

Abstract

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10–expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1–/– mice, but not Rag1–/– IL2rg–/– mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.

Authors

Babak Baban, Molly Braun, Hesam Khodadadi, Ayobami Ward, Katelyn Alverson, Aneeq Malik, Khoi Nguyen, Skon Nazarian, David C. Hess, Scott Forseen, Alexander F. Post, Fernando L. Vale, John R. Vender, Md. Nasrul Hoda, Omid Akbari, Kumar Vaibhav, Krishnan M. Dhandapani

×

Figure 4

Immunometabolic regulation of ILCs after TBI.

Options: View larger image (or click on image) Download as PowerPoint
Immunometabolic regulation of ILCs after TBI. (A) Phosphorylated AMPKα1 ...
(A) Phosphorylated AMPKα1 (p-AMPKα1), a measure of AMPK activation, was assessed in meningeal cells at 24 hours after sham/TBI in WT mice. Isolated meninges were assessed by forward scatter (FSC)/side scatter (SSC), and selected populations were further analyzed for p-AMPKα. Scatterplots depicting the % total p-AMPKα+ cells are indicative of suppressed AMPK activation within the meninges after TBI. (B) AMPKα1–global KO (AMPKα1–/–) mice showed higher frequencies of all ILC subtypes after TBI, as compared with WT mice, with most pronounced increases noted for ILC1 and ILC3. (C) Intracisternal administration of IL-33 (1 μg) increased meningeal expression of p-AMPKα after TBI, as compared with placebo treatment in both WT mice and in Rag1–/– mice, which lack mature B and T lymphocytes, but possess functional ILC. Conversely, p-AMPKα was unaffected by IL-33 treatment in Rag1–/– IL2rg–/– mice, which lack both mature lymphocytes and ILC2. (D) Intracisternal administration of IL-33 (1 μg) increased meningeal expression of ILC2 and suppressed both ILC1 and ILC3 expansion at day 5 after TBI in WT and Rag1–/– mice, as compared with placebo (PBS). In contrast, IL-33 did not affect ILC number in Rag1–/– IL2rg–/– mice, which lack ILC2. Meningeal tissue was analyzed by flow cytometry. (E) The stimulatory effects of intracisternal IL-33 on ILC2 frequency were lost in AMPKα1–/– mice, as compared with WT mice. For all panels, quantified data are presented as the mean ± SD from n = 6 mice/group. For each panel, data were compared within each ILC subtype using a 2-tailed Student’s t test (*P < 0.05, **P < 0.01, ****P < 0.0001).