Acidosis Drives Damage-associated Molecular Pattern (DAMP)-induced Interleukin-1 Secretion via a Caspase-1-independent Pathway

The proinflammatory cytokine IL-1 is a key mediator of inflammatory responses that contribute to and exacerbate brain injury. IL-1 is synthesized by microglia in the brain as an inactive precursor (pro-IL-1). Cleavage of pro-IL-1 to a mature form is stimulated by damage-associated molecular patterns (DAMPs). These DAMPs are sensed by a pattern recognition receptor called NLRP3, which forms an inflammasome, resulting in the activation of caspase-1 and cleavage of pro-IL-1. To date, regulation of the inflammasome in culture has been studied under normal culture conditions, and it is not known how DAMPs signal under disease relevant conditions such as acidosis. Given the presence of acidosis in pathological states, our objective was to test the hypothesis that acidic conditions modify DAMP-induced IL-1 release from cultured primary mouse glial cells. When LPS-primed glial cells were stimulated with DAMPs under acidic conditions (pH 6.2), the predominant IL-1 form secreted was the 20-kDa rather than the 17-kDa caspase-1-dependent species. Lactic acidosis, induced by the addition of 25 mm lactic acid, also induced the release of 20-kDa IL-1. This 20-kDa product was produced independently of NLRP3 and caspase-1 but was inhibited by the cathepsin D inhibitor pepstatin A. These data suggest that under disease relevant acidosis, DAMPs and lactic acid induce the secretion of IL-1 independently of the inflammasome. Therapeutic strategies directed to the inhibition of IL-1 processing should therefore consider alternative processing of IL-1 in addition to caspase-1-dependent processing.