ILC2 modulation via Nmur1 signaling and NMU
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Solution Overview
Problem
The balance between homeostatic and pathological Type 2 innate lymphoid cell (ILC2) responses is unclear, and there are no known markers to distinguish between homeostatic and pro-inflammatory ILCs, making it challenging to modulate their responses effectively in allergic inflammation and asthma.
Innovation Solution
The identification of the neuropeptide receptor Nmur1 as selectively expressed on ILC2s and the use of neuromedin U (NMU) to modulate ILC2 responses, with co-administration of IL-25 amplifying allergic lung inflammation and inducing specific ILC2 subsets characterized by a pro-inflammatory molecular signature.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If alarmin cytokines (IL-25 and IL-33) are used to activate ILC2s, then tissue homeostasis is promoted, but allergic inflammatory responses are also initiated
Solution Approach 1:
The patent identifies distinct functional states within ILC2 populations through single-cell genomics, revealing that different subsets of ILC2s exhibit different responses to alarmin cytokines. Homeostatic ILC2s and pro-inflammatory ILC2s can be distinguished by their transcriptional profiles and response patterns to IL-25 and IL-33, allowing for selective modulation of specific subsets rather than uniform activation of all ILC2s.
Solution Approach 2:
The invention segments the ILC2 population into functionally distinct subsets based on single-cell RNA sequencing data. This segmentation reveals that not all ILC2s respond equally to alarmin stimulation, and identifies specific molecular markers that define homeostatic versus pro-inflammatory states, enabling targeted therapeutic approaches.
2Measurement precision
If single-cell genomics is used to identify ILC subsets, then previously unrecognized subpopulations are discovered, but the functional roles of these subpopulations remain unclear
Solution Approach 1:
The patent employs a feedback approach by using single-cell genomics to identify novel ILC2 subsets, then experimentally testing their functional responses to alarmin cytokines. The functional data feeds back into refining the molecular characterization of these subsets, creating an iterative process that simultaneously improves identification precision and clarifies functional roles.
Solution Approach 2:
The invention uses transcriptional markers and molecular signatures as intermediaries to bridge the gap between identifying ILC2 subsets and understanding their functions. These molecular markers serve as proxies that link the structural identification of cell subsets to their functional behavior in response to inflammatory stimuli.
3Productivity
If ILC2s are activated to drive allergic inflammation, then effector cytokines (IL-5 and IL-13) are produced, but tissue homeostasis is compromised
Solution Approach 1:
The patent identifies specific transcriptional parameters and molecular signatures that distinguish homeostatic from pro-inflammatory ILC2 states. By targeting these parameter changes through therapeutic intervention, it is possible to shift ILC2s from a pro-inflammatory state (high effector cytokine production) back to a homeostatic state (tissue protection), effectively reversing the harmful effects while preserving beneficial functions.
Data Source
AI summary
Computational and functional analysis identified the neuropeptide receptor Nmur1 as selectively expressed on Type 2 innate lymphoid cells (ILC2s). While both IL-33 and IL-25 promote ILC activation in vivo, IL-33 induces robust ILC proliferation, whereas ILCs activated with IL-25 do not proliferate as robustly and up-regulate Nmur1 expression. Treatment with neuromedin U (NMU), the neuropeptide ligand of Nmur1, had little effect on its own. Co-administration of IL-25 with NMU, however, dramatically amplified allergic lung inflammation and induced the proliferation and expansion of specific ILC2 subsets, characterized by a molecular signature unique to pro-inflammatory ILC2s. The results demonstrate that Nmur1 signaling strongly modulates IL-25-mediated ILC2 responses, resulting in highly proliferative pro-inflammatory ILCs, and highlights the importance of neuro-immune crosstalk in allergic inflammatory responses at mucosal surfaces.