Interleukin 33 signaling beneficially regulates pathologic glia in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune condition characterized by a relapsing-remitting or progressive course of demyelination and neuron injury, leading to irreversible neurologic disability. While modern therapies reduce MS relapses, there are no available treatments that markedly slow progression or improve remyelination in MS. Recent studies suggest that pathologic immune–glia interactions play a key role in progressive MS. Chronic inflammation transforms astrocytes into reactive astrocytes, which can be toxic to neurons, and impairs remyelination mediated by oligodendrocyte precursor cells (OPCs). The mechanisms that regulate pathologic immune-glial responses in MS are incompletely understood. Interleukin (IL)-33 is a regulatory cytokine and alarmin that promotes protective immune activation, wound healing, and growth factor production. Interestingly, IL-33 is expressed in the healthy CNS and elevated in people with MS (PwMS). Increased IL-33 correlates with decreased lesion burden in PwMS, and IL-33 improves recovery in the mouse model experimental autoimmune encephalitis (EAE), but the underlying beneficial mechanism(s) of IL-33 in neuroinflammation are not fully understood. In other systems, IL-33 is known to potently activate regulatory T cells (Tregs), triggering downstream events including production of the growth factor amphiregulin. In this proposal, I seek to establish IL-33–induced amphiregulin as a therapeutic target to halt progression and promote remyelination in MS. In Aim 1 I will investigate IL-33 mediated Treg activation in EAE. I hypothesize that IL-33 activates Tregs to produce amphiregulin, improving recovery and reducing pathologic reactive astrocytes. I will use transgenic animals where Tregs cannot detect IL-33 and cutting-edge single cell RNA sequencing techniques to characterize the impact on glia cell phenotypes. Aim 2 will test the potential for amphiregulin to enhance remyelination. I will expand on preliminary data showing that recombinant amphiregulin enhances OPC differentiation in vitro. To study myelination in vivo, I will employ an MS-relevant mouse model of demyelination, adoptive transfer cuprizone, using transgenic mice lacking amphiregulin. Finally, IL-33 signaling is blocked by an endogenous decoy receptor called sST2, and my preliminary data showed increased sST2 in the plasma of progressive MS patients. In Aim 3 I will test a novel small molecule that blocks sST2 in EAE. This compound releases the inhibition on IL-33, which I predict will have a beneficial effect through Treg activation and decreased pathologic glia. I will characterize the CNS penetration, pharmacokinetics, and disease impact of this molecule. Throughout this proposal, I strive to employ disease relevant models and readouts that will be instructive for future clinical translation. Completing these aims will advance our knowledge of a promising pathway— IL-33 signaling—to target disease mechanisms in MS that are not addressed by available therapies. Additionally, the proposed training plan, mentorship team, and research aims seamlessly complement one another to facilitate my transition to independence. Project Number: 1K08AI196474-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Sachin Gadani | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $157,788 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 IIDA-T (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08AI19647401