NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Area of Science:

• Immunology
• Allergy and Asthma Research
• Innate Immune Memory

Background:

• Group 2 innate lymphoid cells (ILC2s) can develop memory, but the mechanisms governing ILC2 memory induction and trained immunity remain unclear.
• High expression of NFκB1 in ILC2s suggests a potential role in these processes.

Purpose of the Study:

• To investigate the role of NFκB1 in ILC2 memory induction and memory-driven effector functions within a mouse model of asthma.
• To elucidate the molecular mechanisms underlying NFκB1's function in ILC2-mediated allergic inflammation.

Main Methods:

• Asthma model induction via intranasal Alternaria administration.
• Assessment of immune responses using flexivent, ELISA, histology, real-time PCR, western blot, flow cytometry, and immunofluorescence staining.

Main Results:

• NFκB1 is crucial for the effector phase of memory-driven asthma, promoting IL33 production, ILC2 generation, and type-2 cytokine release, leading to eosinophilic inflammation.
• NFκB1's role in type-2 cytokine induction by ILC2s is independent of GATA3.
• NFκB1 also influences allergen-induced ILC3s and FoxP3+ Tregs but not Th2 cells.
• Conversely, NFκB1 antagonizes memory induction by inhibiting memory-associated gene upregulation in ILC2s and promotes RUNX1 upregulation, forming a heterodimer with RUNX1.

Conclusions:

• NFκB1 exhibits a dual role, positively regulating the effector phase while inhibiting the memory induction phase in ILC2s.
• An interdependent antagonism exists between memory induction and effector processes.
• The NFκB1-RUNX1 heterodimer acts as a non-canonical transcriptional activator of type-2 cytokines in ILC2s.