AMPK induces regulatory innate lymphoid cells after traumatic brain injury

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere126766
JournalJCI Insight
Volume6
Issue number1
DOIs
StatePublished - Jan 11 2021

ASJC Scopus subject areas

  • Medicine(all)

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