An Interactive Journey Through Innate Immunity
TLR4 detects lipopolysaccharide through MyD88-dependent and TRIF-dependent signaling, triggering cytokine production and interferon responses. Recent evidence shows TLR8 dominates over TLR7 in neutrophil activation by RNA-immune complexes in SLE.
FPR1 responds to fMLF while FPR2 recognizes phenol-soluble modulins from S. aureus. These Gαi-coupled receptors activate phospholipase C, mobilize calcium, and enhance phagocytosis through upregulation of complement and Fcγ receptors.
CR1 (CD35) serves as the primary receptor for C3b-opsonized particles, challenging previous assumptions about CR3 dominance. Mac-1 (CR3) provides additional activation signals and regulates neutrophil adhesion and migration.
FcγRIIa mediates IgG-dependent phagocytosis through Syk kinase recruitment. FcγRIIIb triggers distinct PKC isoforms and preferentially drives NET formation. IgA-FcαRI interactions elicit superior cytotoxicity compared to IgG-FcγR signaling.
CXCR2 and CXCR4 antagonistically regulate neutrophil mobilization from bone marrow. CXCR4-CXCL12 provides retention signals while CXCR2 activation by ELR+ chemokines promotes egress into circulation.
Arp2/3 nucleates branched actin networks while formins generate linear filaments. Profilin delivers ATP-actin for polymerization and cofilin severs ADP-actin, sustaining rapid treadmilling essential for migration.
Rab GTPases orchestrate sequential fusion events: Rab5 recruits EEA1, Rab7 mediates lysosome fusion, and Rab14/Rab2 cooperate with Rab7. Rab35 defines a parallel pathway for apoptotic cell degradation.
Four granule classes release hierarchically: secretory vesicles → tertiary → secondary → primary. SNARE proteins control fusion specificity, with SNAP-23/syntaxin 6 regulating secondary granule exocytosis.
NOX2 complex assembly requires p47phox phosphorylation and Rac2-GTP binding to p67phox. Electron transfer from NADPH through FAD and heme generates superoxide. Glycolysis and pentose phosphate pathway sustain NADPH supply.
Lytic NETosis requires ROS and PAD4-mediated histone citrullination. Elastase and myeloperoxidase process chromatin for release. PI3Kα/γ drive NET generation, with Syk coordinating upstream activation signals.
Receptor engagement triggers immediate signaling: calcium mobilization, PKC activation, and F-actin polymerization peaks within 10 seconds of chemotactic stimulation.
NADPH oxidase assembly generates ROS burst. Pseudopod extension around opsonized targets. Degranulation releases antimicrobial peptides and enzymes. LPS priming increases response capacity.
Abluminal crawling on pericyte processes before basement membrane breach. Transendothelial migration induces phenotypic changes including GRK2 upregulation.
Lytic NETosis releases decondensed chromatin decorated with histones and antimicrobial proteins. Phagosome-lysosome fusion completes pathogen degradation.
Late priming effects manifest: upregulation of adhesion molecules (CD54), pattern recognition receptors (dectin-2), and sustained enhanced responsiveness to activating stimuli.
RNA-immune complexes activate neutrophils through TLR8 (not TLR7), triggering NET formation. MICL autoantibodies disrupt inhibitory feedback, causing excessive NETosis and worsened outcomes.
Dysregulated MICL signaling due to blocking autoantibodies results in uncontrolled NET generation. Neutrophil-derived NETs drive chronic inflammation and joint destruction.
Tumor-associated neutrophils exhibit N2 polarization promoting immunosuppression. NETs capture circulating tumor cells facilitating metastasis, awaken dormant cells, and shield tumors from immune surveillance.
S. aureus phenol-soluble modulins activate FPR2, driving enhanced phagocytosis through complement/Fcγ receptor upregulation. Diverse bacteria elicit distinct neutrophil response patterns.
Neutropenic patients suffer invasive candidiasis and aspergillosis. NETs contain hyphal structures too large for phagocytosis. Chronic granulomatous disease patients lack oxidative burst and experience recurrent fungal infections.
SARS-CoV-2 proteins engage TLRs and complement receptors inducing NETs that contribute to COVID-19 pathology through microthrombus formation and endothelial injury.
Reduce aberrant neutrophil activation, NET formation, and tissue infiltration in autoimmune diseases. Disrupt macrophage-IL-1β-neutrophil inflammatory loops.
PI3Kγ inhibition suppresses NETosis and reduces aneurysm progression. Isoform-selective targeting modulates specific neutrophil functions while preserving others.
Limit neutrophil recruitment to inflammatory sites while preserving circulating counts through CXCR4-mediated retention. Clinical trials ongoing for IBD and COPD.
Enhanced FcγR engagement improves neutrophil-mediated tumor killing and mycobacterial control. IgA-based therapeutics leverage superior FcαRI signaling.
DNase degrades extracellular DNA scaffolds reducing pathology in sepsis and thrombosis. PAD4 inhibitors prevent NET formation but risk impairing antimicrobial defense.
Resolvins, protectins, and maresins accelerate neutrophil apoptosis and enhance efferocytosis. Efficacy demonstrated in acute lung injury and peritonitis models.