C3a Is Required for the Production of CXC Chemokines by Tubular Epithelial Cells after Renal Ishemia/Reperfusion

Abstract

The complement system is one of the major ways by which the body detects injury to self cells, and the alternative pathway of complement is rapidly activated within the tubulointerstitium after renal ischemia/reperfusion (I/R). In the current study, we investigate the hypothesis that recognition of tubular injury by the complement system is a major mechanism by which the systemic inflammatory response is initiated. Gene array analysis of mouse kidney following I/R initially identified MIP-2 (CXCL2) and keratinocyte-derived chemokine (KC or CXCL1) as factors that are produced in a complement-dependent fashion. Using in situ hybridization, we next demonstrated that these factors are expressed in tubular epithelial cells of postischemic kidneys. Mouse proximal tubular epithelial cells (PTECs) in culture were then exposed to an intact alternative pathway and were found to rapidly produce both chemokines. Selective antagonism of the C3a receptor significantly attenuated production of MIP-2 and KC by PTECs, whereas C5a receptor antagonism and prevention of membrane attack complex (MAC) formation did not have a significant effect. Treatment of PTECs with an NF-κB inhibitor also prevented full expression of these factors in response to an intact alternative pathway. In summary, alternative pathway activation after renal I/R induces production of MIP-2 and KC by PTECs. This innate immune system thereby recognizes hypoxic injury and triggers a systemic inflammatory response through the generation of C3a and subsequent activation of the NF-κB system.

TLR2 Signaling in Tubular Epithelial Cells Regulates NK Cell Recruitment in Kidney Ischemia–Reperfusion Injury

“…To manage these stressful conditions (17), they have numerous sensors, many of which converge on inflammation. Well-known examples are the TLR and complement systems (4)(5)(6)(7)(8)20). Individual signaling through TLR2, TLR4, and complement receptors results in proinflammatory cytokine and chemokine production (20).…”

“…Well-known examples are the TLR and complement systems (4)(5)(6)(7)(8)20). Individual signaling through TLR2, TLR4, and complement receptors results in proinflammatory cytokine and chemokine production (20). This result, however, does not mean that they have redundant roles in kidney IRI (6,20).…”

Candidate inhibitors of porcine complement

“…C3a is also found to have importance in other inflammatory conditions, like I/R-injury in the kidneys (77). C5a is the key inflammatory mediator of the anaphylatoxins and probably of all the complement components.…”

Ischaemia Reperfusion Injury in Kidney Transplantation

“…Consistent with this finding, mice deficient in Crry are more susceptible to kidney IRI. C3a also has a role in the production of CXC chemokines by tubular epithelial cells observed after IRI (Thurman, Lenderink et al 2007). C5a and the membrane attack complex (C5b-9) are implicated in kidney IRI and inhibition of C5a confers protection (Zhou, Farrar et al 2000;Arumugam, Shiels et al 2003;De Vries, Matthijsen et al 2003).…”