Spingosine-1-phosphate receptor 1 agonist alleviates hypersensitivity pneumonitis induced by Methanosphaera stadtmanae

Abstract

Abstract Hypersensitivity pneumonitis (HP) is characterized by the formation of B cell-rich tertiary lymphoid tissue (TLT) in the lung, and by a granulocytic response upon antigen rechallenge. Clinically, antigen avoidance is the only effective approach to manage HP symptoms and progression. Sphingosine-1-phosphate receptor 1 (S1PR1) regulates key mechanisms underlying the formation of TLTs such as lymphocyte trafficking and intercellular interactions. Given that TLTs are key to the antigen-specific response in the lung, we investigated the impact of an S1PR1 agonist on pulmonary TLTs accumulation and determined the effect of quantitative TLTs modulation on the granulocytic response to an antigen rechallenge. Experimental HP was induced in mice using intranasal instillations of an immunogenic archaea found in farm bioaerosol, Methanosphaera stadtmanae (MSS), for 3 weeks. After a 48 hours resting period, mice were treated for 7 days with the S1PR1 agonist, RP001 (1mg/kg/day), or its vehicle using osmotic pumps. Five days after treatment initiation, mice were either euthanized, rechallenged with saline or rechallenged with MSS. Mice were euthanized 48h later to quantify pulmonary TLTs and inflammatory cells. RP001 did not influence TLTs accumulation and lung inflammation prior to MSS rechallenge. After MSS rechallenge, RP001 reduced the accumulation of TLTs by 49% (p=0.02) and reduced neutrophil accumulation by 39% (p=0.002), when compared to vehicle. Thus, S1PR1 modulation, after the initiation of a HP-like disease, alleviated TLTs accumulation along with the neutrophilic response to an antigen rechallenge. Our results support the concept that S1PR1 modulation can interfere with mechanisms that sustain HP.