Protein Kinase C δ: a critical hub regulating macrophage immunomodulatory functions during Mycobacterium tuberculosis infection

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Abstract A host-modulating candidate gene involved in putative pathogen-killing pathways, with potential novel therapeutic intervention, Protein Kinase C – δ (PKCδ) has been recognized as a critical marker of inflammation with clinical and experimental evidence in recent years. Pulmonary microenvironment during Mtb infection is largely governed by lung resident macrophages, initiating innate and subsequent adaptive immune responses. We investigated the role of PKCδ in macrophages using a macrophage-specific PKCδ knockout mice model (LysM cre PKCδ flox/flox ). PKCδ deficiency in macrophages triggers an early lymphocytic immune response, increases neutrophil recruitment, and reduces inflammatory macrophages in the lungs, leading to higher Mtb burden and exacerbated pathology. Experimental and omics analysis further revealed that dysregulation of antimicrobial effector functions is detrimental to macrophage’s ability to restrict bacterial growth in vitro . Importantly this defect was mitigated by exogenous GM-CSF supplementation and/or overexpressing PKCδ in macrophages. Thus, PKCδ plays a crucial role in immune modulation during Mtb infection with GM-CSF amongst several downstream pathways through which PKCδ exerts its regulatory effects. Teaser PKCδ is crucial for immune modulation during Mtb infection revealing macrophages as a potential axis of signaling.

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