Interleukin (IL)-1α and IL-1β are pro-inflammatory cytokines mainly released by monocytes and macrophage in response to infection. Upon release, IL-1α/β bind to IL-1 receptor type 1 (IL-1R1) initiating a pro-inflammatory signaling pathway, which leads to the release of several inflammatory mediators. Dysregulation of IL-1α/β production is associated to the pathogenesis of several disorders, including sepsis, cancer and autoinflammatory diseases.

The release of cytokines of the IL-1 family requires inflammasome-mediated caspase-1 activation. The inflammasome is a multi-protein complex that senses danger and microbial signals promoting the production of IL-1β, IL-18 and partially of IL-1α. The activation of the NLRP3 inflammasome is generally regulated by a two-step pathway: first, the cells have to be primed through the activation of NF-κB, inducing the expression of pro-IL-1β and NLRP3; second, an additional stimulus is required to induce the inflammasome complex formation, which in turn leads to the activation of caspase-1 and the subsequent cleavage of pro-IL-1β and pro-IL-18. Human monocytes do not follow this dual mode of activation inasmuch they release IL-1α/IL-1β when stimulated with lipopolysaccharide (LPS) alone in absence of any proper inflammasome activator. Recently, an alternative mechanism of NLRP3 inflammasome activation driven by the murine inflammatory caspase-11 by LPS has been described.

We investigated at molecular level the role of the inflammatory caspase-5 in monocyte in response to LPS stimulation. We identified caspase-5 as key immune effector of NLRP3 inflammasome activation in response to LPS in human monocytes. We also elucidated the pathway leading to caspase-5 activation and the subsequent cytokine release. In this new scenario, we proposed caspase-5 as a new candidate target for future therapeutic strategies aimed at limiting excessive inflammatory response.