Complement Anaphylatoxin C5a-Induced Mouse Lymphatic Functions Modulate Interactions Between Endothelial Cells and T Lymphocytes

The lymphatic system is a highly branched endothelial tubular network that facilitates the migration of immune cells from the peripheral tissues to lymph nodes (LNs) and other lymphoid organs. Complement factors are essential for innate and adaptive immune functions. Complement anaphylatoxin C5a is crucial in vascular endothelial cell activation and lymphocyte polarization. Understanding the impact of C5a and its cognate receptor C5ar1 signaling on lymphatic function could provide new insights into the mechanisms of immune dysregulation observed in chronic inflammatory diseases. We demonstrate that acute C5a challenge in wildtype C57B6/J mice significantly reduced lymph propulsion compared to their C5ar1-deficient counterparts. C5ar1-dependent attenuation of lymph propulsion with LPS challenge corroborated with significantly increased endothelial-derived inducible nitric oxide synthase (iNOS) expression. C5ar1-iNOS axis modulated T helper cell polarization towards Cd4⁺/Ccr5⁺ Th1 subtypes, indicating that C5a-activated endothelial-iNOS may contribute to Th1 polarization in the peripheral LNs during homing. Finally, we observed C5a-mediated endothelial surface glycoprotein CD146 interaction with Th1 cell intermediate filament protein vimentin that may facilitate transmigration of activated Th1 cells into systemic circulation and tissue interstitium. Given the critical role of the C5a/C5ar1 axis in promoting lymphatic dysfunction, our study highlights the therapeutic potential of targeting C5ar1 in chronic inflammatory conditions.