Th171 - Mitochondrial Derived ATP and Its Metabolites Modulate the Balance of B-cell Cytokine Responses: Implications for MS Pathogenesis and Therapeutics

Ayman Rezk – Department of Neurology – University of Pennsylvania; Diego Espinoza – Department of Neurology – University of Pennsylvania; Huiru Feng – Institute of Immunotherapy – Fujian Medical University; Bo Zhang – Institute of Immunotherapy – Fujian Medical University; amit Bar-Or – Department of Neurology – University of Pennsylvania

Abstract Text: Among key antibody-independent B-cell functions are their capacity for context-dependent secretion of distinct cytokine profiles that can shape local immune responses in both health and disease. Abnormal B-cell cytokine responses have now been implicated in the pathophysiology of multiple human immune-mediated conditions, including multiple sclerosis (MS). Surprisingly little is known, however, about the mechanisms involved in the regulation of B-cell cytokine expression. Our goal was to investigate fundamental mechanisms underlying regulation of the balance between B-cell pro- and anti-inflammatory cytokine responses and their impact on CNS inflammation. We find that B-cell cytokine production is metabolically regulated both in vitro and in vivo, with particular involvement of mitochondrial respiration (OXPHOS), and that distinct modes of B-cell activation shift their metabolic state, regulate the extent of ATP release by the B cells, and trigger the coordinated and modular regulation of ATP-pathway molecular machinery that enables ATP and its metabolites to function as a ‘4th signal’, that reciprocally modulates the balance between pro- and anti- inflammatory cytokine expression. We further find that inhibition of either B-cell OXPHOS or ATP signaling could attenuate CNS inflammation in vivo, as well as restore the balance of B-cell cytokine responses in MS. Furthermore, we demonstrate that BTK inhibition, an emerging B-cell-targeting autoimmune disease therapeutic approach, could modulate B-cell cytokine responses through decreasing OXPHOS. Together, our study reveals a fundamental mechanism involving metabolic regulation of B-cell pro- and anti-inflammatory cytokine responses and points to non-depleting therapeutic strategies that restore the B-cell cytokine balance in MS by targeting metabolism.