UC San Diego

Type 2 inflammation plays a critical role in most asthmatic cases and may be affected during recurring viral and bacterial infections. The presence of intracellular pathogens promotes the buildup of danger signaling cyclic-di-nucleotide molecules such as cyclic-di-GMP (CDG), a bacterial second messenger. Group 2 innate lymphoid cells (ILC2s) are major contributors to type 2 inflammatory responses after exposure to fungal allergens yet the role of CDG in regulating pulmonary ILC responses in inflammation remains to be seen. Our studies demonstrate that intranasal exposure to CDG drives early type 1 interferon (IFN) production and effectively suppresses type 2 lung inflammation and CD127+ST2+ ILC2s during Alternaria challenge in a STING-cGAS dependent manner. Interestingly, CDG drove activation and expansion of ST2-CD127- pulmonary ILCs, which exhibit a transcriptomic profile consistent with ILC1s. Overall, CDG has demonstrated a suppressive effect on type 2 inflammatory responses while simultaneously promoting ILC1 activation. Our findings suggest that there is potential to utilize STING to mediate type 2 inflammatory responses and/or promote anti-viral immunological mechanisms.