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Interleukin 33 signaling beneficially regulates pathologic glia in multiple sclerosis

Award Number: K08AI196474
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/06/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Interleukin 33 signaling beneficially regulates pathologic glia in multiple sclerosis - Project Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $157,788 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	4/6/2026	NEW	$157,788
														Subtotal = $157,788

Grand Total All Awards = $157,788

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Interleukin 33 signaling beneficially regulates pathologic glia in multiple sclerosis

Award Number: K08AI196474

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/06/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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