TY - JOUR
T1 - AMPK induces regulatory innate lymphoid cells after traumatic brain injury
AU - Baban, Babak
AU - Braun, Molly
AU - Khodadadi, Hesam
AU - Ward, Ayobami
AU - Alverson, Katelyn
AU - Malik, Aneeq
AU - Nguyen, Khoi
AU - Nazarian, Skon
AU - Hess, David C.
AU - Forseen, Scott
AU - Post, Alexander F.
AU - Vale, Fernando L.
AU - Vender, John R.
AU - Nasrul Hoda, Md
AU - Akbari, Omid
AU - Vaibhav, Kumar
AU - Dhandapani, Krishnan M.
N1 - Funding Information:
We acknowledge the technical assistance of Jeanene Pihkala for flow cytometry. This work was supported by grants from the NIH (NS110378 to KMD/BB, NS117565 to KMD, and NS114560 to KV).
Publisher Copyright:
Copyright: © 2021, Baban et al.
PY - 2021/1/11
Y1 - 2021/1/11
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.126766
DO - 10.1172/jci.insight.126766
M3 - Article
C2 - 33427206
AN - SCOPUS:85099712943
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 1
M1 - e126766
ER -