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Acetaminophen (APAP) is a widely used drug known for its analgesic and antipyretic properties. However, its exact mechanism of action is still unclear and has been primarily associated with its effects on COX enzymes and serotonergic pathways. Till date, the immunological mechanisms affected by APAP has gained only inadequate attention. A distinct group of immune cells called Group 2 Innate Lymphoid Cells (ILC2s) are known to play an important role in type 2 cytokine-mediated immunity and their regulatory dysfunction is associated with numerous type 2 pathologies, such as allergy. Conversely, another class of recently characterized Innate Lymphoid Cells called Innate Regulatory Cells (ILCregs) suppress the activation of ILC2s. Maintaining a balance between ILC2s and ILCregs is vital for achieving a well-controlled immune response and tissue homeostasis. Recent studies have highlighted the critical role of prostaglandin D2 (PGD2) in the maturation and development of ILC2 functions. Since APAP also suppresses PGD2 synthesis, it was speculated that APAP treatment could reduce the number of ILC2s while potentially increasing the number of ILCregs. To investigate this hypothesis, here, we administered therapeutic doses of APAP to OVA-sensitized mice, a well-established model of type 2 pathological inflammation. The mice received oral doses of 200 mg/kg body wt. of APAP twice weekly, along with weekly OVA sensitizations for six weeks. The mice were sacrificed at different time points (days 14, 28 and 42) to assess the kinetics of ILC2s, ILCregs and immunoglobulins (IgE and IgG1). The results demonstrated that APAP treatment effectively suppressed OVA-induced ILC2s while significantly increasing the number of IL-10+ ILCregs. APAP exposure also led to decreased levels of serum PGD2, OVA-specific IgE and IgG1, and enhanced the level of IL-10 in OVA sensitized mice. Moreover, OVA sensitized mice treated with APAP did not develop pathological changes in spleen, when compared to OVA sensitized mice. Additionally, APAP treatment did not cause any adverse effects on mice liver in treatment groups. These preliminary findings suggest that APAP exhibits the capacity to modulate type 2 immune responses by suppressing ILC2s and inducing the expansion of IL-10+ ILCregs. [ABSTRACT FROM AUTHOR]