SIRPa-CD47 axis regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism.

Type-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPa), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPa, and the interaction between SIRPa and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the efficacy of SIRPa in regulating ILC2-mediated AHR, we utilized SIRPa and CD47 deficient mice in a murine model of allergen-induced AHR. Our findings suggest that the absence of SIRPa leads to the overactivation of ILC2s. Conversely, engagement with SIRPa reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPa-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-?B activity and the production of type two cytokines. Additionally, our studies on human cells have revealed that SIRPa is inducible and expressed on human ILC2s, and administration of a SIRPa agonist effectively suppresses the effector function and cytokine production of ILC2s. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviated AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPa-CD47 axis in the treatment of ILC2-dependent allergic asthma. Overall design: mRNA profiles of mouse lung ILC2s from WT and SIRP KO mice were generated by deep sequencing, in duplicates, using a NextSeq 500.