Abstract
Tec family kinases are intracellular non-receptor tyrosine kinases implicated in numerous functions, including T cell and B cell regulation. However, a role in microbial pathogenesis has not been described. Here, we identified Tec kinase as a novel key mediator of the inflammatory immune response in macrophages invaded by the human fungal pathogen C. albicans. Tec is required for both activation and assembly of the noncanonical caspase-8, but not of the caspase-1 inflammasome, during infections with fungal but not bacterial pathogens, triggering the antifungal response through IL-1β. Furthermore, we identify dectin-1 as the pathogen recognition receptor being required for Syk-dependent Tec activation. Hence, Tec is a novel innate-specific inflammatory kinase, whose genetic ablation or inhibition by small molecule drugs strongly protects mice from fungal sepsis. These data demonstrate a therapeutic potential for Tec kinase inhibition to combat invasive microbial infections by attenuating the host inflammatory response.
Highlights
The host defense machinery of the innate immune system exploits highly dynamic mechanisms that respond and eliminate microbial infections
Tec kinase is expressed in the myeloid lineage, including dendritic cells, neutrophils and macrophages [13]
We investigated whether Tec is involved in the inflammatory response and whether loss of Tec would cause any significant changes
Summary
The host defense machinery of the innate immune system exploits highly dynamic mechanisms that respond and eliminate microbial infections. Cells of the innate immune system express germline-encoded pattern recognition receptors (PRRs). The hallmark pro-inflammatory cytokine interleukin-1b (IL-1b) is an important mediator of inflammatory responses during many microbial infections. It has been implicated in the pathophysiology of many infectious diseases as well as auto-immune disorders [3,4]. A second stimulus triggers maturation of inactive pro-IL-1b into active IL-1b, which is released into the extracellular space via a non-classical secretory pathway, resulting in local or systemic inflammation and recruitment and activation of other migratory immune cells from distant body sites, including hematopoietic reservoirs such as bone marrow [6,7].
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