Progranulin as a context-dependent regulator of innate immunity in bacterial infections.

The outcome of bacterial infections depends on a delicate balance between effective pathogen clearance and the containment of immune-mediated damage. Disruption of this equilibrium promotes both microbial persistence and immunopathology, a phenomenon particularly relevant in severe respiratory infections and chronic diseases such as tuberculosis. In this context, progranulin (PGRN) has emerged as a key regulator of the innate immune response. PGRN is a secreted glycoprotein with pleiotropic functions in inflammation, tissue repair, and cell survival, exerting its effects through modulation of central pathways such as tumor necrosis factor (TNF)-α signaling, NF-κB activation, inflammasome activity, and autophagy. However, its biological effects are mechanistically context dependent. While PGRN can limit excessive inflammation and tissue damage by attenuating proinflammatory signaling and cell death pathways, it may also impair antimicrobial mechanisms, including macrophage activation and autophagic responses, thereby favoring pathogen persistence in certain settings. This dual behavior is further influenced by the type of pathogen, the affected tissue, and the stage of the immune response. In this review, we integrate current evidence to propose a framework in which PGRN operates at the interface between host defense and immunopathology. We examine its role across bacterial infections, with particular emphasis on pulmonary immunity, and discuss tuberculosis as a paradigmatic model in which regulatory pathways controlling inflammation are essential for both containment and disease progression. Finally, we address current knowledge gaps and evaluate the potential of PGRN as a biomarker and therapeutic target, highlighting the need for context-specific interpretation prior to clinical application.