Lipoxin A4 restrains mast cell function and inhibits type 2 mediated cutaneous inflammation

Abstract Atopic dermatitis (AD) is a frequently occurring allergic inflammatory disease. In AD, IgE-activated dermal mast cells amplify type 2 immune responses. Current MC-therapies have limited success, necessitating exploration of MC-targeting agents for AD treatment. Lipoxin A4 (LXA4) is an immunoresolvin family member derived from arachadonic acid that signals primarily through the formyl peptide receptor 2 (FPR2). Limited reports investigate the relationship between LXA4, MCs and cutaneous inflammation. Here, we tested the hypotheses that LXA4 downregulates MC function and cutaneous inflammation utilizing bone marrow derived (BM)MCs and the murine type 2 skewed, MC-dependent, FITC-contact hypersensitivity model (CHS), respectively. In resting BMMCs, antagonism of FPR2 and pharmacological inhibition of LXA4 synthesis increased IL-6 and IL-13 release, suggesting that resting BMMCs generate LXA4. Exogenous LXA4 inhibited IgE-initiated MC activation, blocking degranulation and IL-13, TNF, and IL-6 release. Mechanistically, exogenous LXA4 blocked STAT5B and NFkB nuclear translocation and reduced mRNA for STAT5 and NFkB transcribed genes. FPR2 antagonists failed to reverse the effects of exogenous LXA4, suggesting that a second inhibitory receptor may be activated by LXA4 in BMMCs. In vivo, LXA4 reduced ear swelling in the MC-dependent FITC-CHS model. Collectively, these data suggest that LXA4 restrains MC function and may be therapeutically beneficial in AD.